EP3551188B1 - Substituierte chinazolinsulfonamide als inhibitoren des thioredoxin-interagierenden proteins (txnip) - Google Patents

Substituierte chinazolinsulfonamide als inhibitoren des thioredoxin-interagierenden proteins (txnip) Download PDF

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EP3551188B1
EP3551188B1 EP18804193.3A EP18804193A EP3551188B1 EP 3551188 B1 EP3551188 B1 EP 3551188B1 EP 18804193 A EP18804193 A EP 18804193A EP 3551188 B1 EP3551188 B1 EP 3551188B1
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alkyl
alkoxy
haloalkyl
dialkylamino
alkylamino
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French (fr)
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EP3551188A1 (de
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Corinne E. Augelli-Szafran
Omar MOUKHA-CHAFIQ
Mark J. Suto
Anath SHALEV
Lance THIELEN
Junqin Chen
Gu JING
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UAB Research Foundation
Southern Research Institute
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Southern Research Institute
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • sequence listing is submitted electronically via EFS-Web as an ASCII formatted sequence listing in a file named 035979_1110651_Seqlist.txt, created on October 29, 2018, having a size of 4.00 kb and filed concurrently with the specification.
  • the sequence listing contained in this ASCII formatted document is part of the specification.
  • Pancreatic ⁇ -cell dysfunction and death play a central role in the development and progression of diabetes and can be caused by multiple stressors including glucotoxicity, (gluco-)lipotoxicity, and cytokine toxicity ( Poitout and Robertson (2002) Endocrinology 143: 339-342 ; Eizirik and Mandrup-Poulsen (2001) Diabetologia 44: 2115-2133 ).
  • Glucotoxicity induced by chronic exposure of ⁇ -cells to high levels of glucose promotes ⁇ -cell apoptosis and, combined with the elevated glucagon levels associated with diabetes ( Unger and Orci (1975) Lancet 1: 14-16 ), results in a vicious cycle with further worsening of the hyperglycemia ( Poitout and Robertson (2002) Endocrinology 143: 339-342 ). It was previously shown that thioredoxin-interacting protein (TXNIP), a ubiquitously expressed cellular redox regulator ( Nishiyama et al. (1999) J. Biol. Chem.
  • TXNIP is a crucial mediator of glucotoxicity-induced ⁇ -cell apoptosis ( Chen et al. (2008) Diabetes 57: 938-44 ). It was further shown that ⁇ -cell TXNIP transcription is upregulated by glucose and its expression is increased in diabetes ( Minn et al. (2005) Endocrinology 146:2397-2405 .) Also, TXNIP-induced ⁇ -cell death is mediated by the intrinsic/mitochondrial death pathway ( Chen et al.
  • TXNIP deficiency led to an increase in functional ⁇ -cell mass and protected against diabetes in mouse models of type 1 (T1D) and type 2 (T2D) diabetes ( Chen et al. (2008) FASEB J. 22: 3581-3594 ).
  • TXNIP deletion has been associated with reduced hepatic glucose production and beneficial effects in extrapancreatic tissues such as kidney, retina and the cardiovascular system in the context of diabetes. Despite the detrimental effects elevated TXNIP plays in diabetes and its associated disorders, prior to the present disclosure there was no known effective way to specifically block TXNIP expression.
  • the invention in one aspect, relates to compositions and methods for use in the prevention and treatment of disorders associated with elevated TXNIP and/or elevated glucagon levels, such as, for example, diabetes and associated disorders (e.g., Type 1 diabetes, Type 2 diabetes, gestational diabetes, impaired glucose control, impaired glucose tolerance or pre-diabetes, insulin resistance, hyperlipidemia, non-alcoholic fatty liver disease, complications of diabetes, including diabetes-related nephropathy, neuropathy, retinopathy, cardiomyopathy, and cardiovascular disease, as well as pancreatic ⁇ -cell loss or pancreatic islet dysfunction, including dysregulation of insulin and/or glucagon production or secretion) or other disorders associated with endoplasmic reticulum stress and/or oxidative stress of the cell.
  • diabetes and associated disorders e.g., Type 1 diabetes, Type 2 diabetes, gestational diabetes, impaired glucose control, impaired glucose tolerance or pre-diabetes, insulin resistance, hyperlipidemia, non-alcoholic fatty liver disease, complications of diabetes, including diabetes-
  • a method for treating a disorder associated with elevated TXNIP or elevated glucagon in a mammal comprising the step of administering to the mammal a therapeutically effective amount of at least one compound having a structure represented by a formula selected from: and wherein n is 0, 1, or 2; wherein p is 0, 1, 2, 3, or 4; wherein q is 0 or 1; wherein R 1 is -NH 2 , - OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, -(C1-C4 alkyl)(C1-C4 alkoxy), -(C1-C4 alkyl)CO 2 H, or Cy 1 ; wherein Cy 1 , when present, is C3-C6 cycloalkyl, C2-
  • Also disclosed is a method for inhibiting TXNIP expression or lowering glucagon levels in a mammal comprising the step of administering to the mammal an effective amount of at least one compound having a structure represented by a formula selected from: and wherein n is 0, 1, or 2; wherein p is 0, 1, 2, 3, or 4; wherein q is 0 or 1; wherein R 1 is -NH 2 , - OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, -(C1-C4 alkyl)(C1-C4 alkoxy), -(C1-C4 alkyl)CO 2 H, or Cy 1 ; wherein Cy 1 , when present, is C3-C6 cycloalkyl, C2-C5 heterocycloal
  • compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one compound having a structure represented by a formula: wherein n is 0, 1, or 2; wherein p is 1, 2, 3, or 4; wherein q is 0 or 1; wherein R 1 is -NH 2 , - OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, -(C1-C4 alkyl)(C1-C4 alkoxy), -(C1-C4 alkyl)CO 2 H, or Cy 1 ; wherein Cy 1 , when present, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen,
  • compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one compound having a structure represented by a formula: wherein n is 0, 1, or 2; wherein q is 0 or 1; wherein R 1 is -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, -(C1-C4 alkyl)(C1-C4 alkoxy), -(C1-C4 alkyl)CO 2 H, or Cy 1 ; wherein Cy 1 , when present, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -NH 2 , -OH, C1-C4
  • compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one compound having a structure represented by a formula selected from: wherein n is 0, 1, or 2; wherein p is 0, 1, 2, 3, or 4; wherein q is 0 or 1; wherein R 1 is -NH 2 , - OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, -(C1-C4 alkyl)(C1-C4 alkoxy), -(C1-C4 alkyl)CO 2 H, or Cy 1 ; wherein Cy 1 , when present, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen,
  • methods for treating a disorder associated with elevated TXNIP or elevated glucagon in a mammal comprising administering to the mammal a therapeutically effective amount of at least one pharmaceutical composition or compound as described herein.
  • methods of lowering hepatic glucose production in a mammal in need thereof comprising administering to the mammal a therapeutically effective amount of at least one pharmaceutical composition or compound as described herein.
  • compositions and methods for use in the prevention and treatment of hyperlipidemia and/or fatty liver disease e.g., nonalcoholic fatty liver disease
  • the disclosed methods include administering to the mammal a therapeutically effective amount of at least one pharmaceutical composition or compound as described herein.
  • Also disclosed but not claimed are methods of identifying an inhibitor of glucose-induced TXNIP expression comprising culturing cells stably transfected with an exogenous TXNIP promoter in a first culture medium containing a low level of glucose; culturing a first subset of the cells of step (a) in a second culture medium containing a high level of glucose; culturing a second subset of the cells of step (a) in a third culture medium containing a high level of glucose and an agent to be tested; and comparing the level of TXNIP promoter activity in the first subset of cells with the level of TXNIP expression in the second subset of cells, wherein a lower level of TXNIP promoter activity in the second subset of cells as compared to the first subset of cells indicates the agent is an inhibitor of glucose-induced TXNIP expression.
  • the method can further comprise determining the identified inhibitor of glucose-induced TXNIP expression is a selective inhibitor of TXNIP expression and not a general transcriptional inhibitor comprising contacting a cell comprising a first and second exogenous promoter with the identified inhibitor of glucose-induced TXNIP expression, wherein the first exogenous promoter is a TXNIP promoter and the second exogenous promoter promotes expression of a non-TXNIP gene; and detecting the level of promoter activity of the TXNIP and the non-TXNIP gene, wherein detecting a reduction in the level of TXNIP promoter-driven gene expression without reduction in the level of non-TXNIP promoter-driven gene expression as compared to a control cell without contact with the inhibitor of glucose-induced TXNIP determines that the identified inhibitor of glucose-induced TXNIP expression is not a general inhibitor of transcription.
  • Ranges can be expressed herein as from “about” one particular value, and/or to "about” another particular value. When such a range is expressed, another aspect includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent "about,” it will be understood that the particular value forms another aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as "about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10" is also disclosed. It is also understood that each unit between two particular units are also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.
  • the terms “about” and “at or about” mean that the amount or value in question can be the value designated some other value approximately or about the same. It is generally understood, as used herein, that it is the nominal value indicated ⁇ 10% variation unless otherwise indicated or inferred. The term is intended to convey that similar values promote equivalent results or effects recited in the claims. That is, it is understood that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but can be approximate and/or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art.
  • an amount, size, formulation, parameter or other quantity or characteristic is “about” or “approximate” whether or not expressly stated to be such. It is understood that where "about” is used before a quantitative value, the parameter also includes the specific quantitative value itself, unless specifically stated otherwise.
  • references in the specification and concluding claims to parts by weight of a particular element or component in a composition denotes the weight relationship between the element or component and any other elements or components in the composition or article for which a part by weight is expressed.
  • X and Y are present at a weight ratio of 2:5, and are present in such ratio regardless of whether additional components are contained in the compound.
  • a weight percent (wt. %) of a component is based on the total weight of the formulation or composition in which the component is included.
  • IC 50 is intended to refer to the concentration of a substance (e.g., a compound or a drug) that is required for 50% inhibition of a biological process, or component of a process, including a protein, subunit, organelle, ribonucleoprotein, etc.
  • a substance e.g., a compound or a drug
  • an IC 50 can refer to the concentration of a substance that is required for 50% inhibition in vivo, as further defined elsewhere herein.
  • IC 50 refers to the half maximal (50%) inhibitory concentration (IC) of a substance.
  • EC 50 is intended to refer to the concentration of a substance (e.g., a compound or a drug) that is required for 50% agonism of a biological process, or component of a process, including a protein, subunit, organelle, ribonucleoprotein, etc.
  • a substance e.g., a compound or a drug
  • an EC 50 can refer to the concentration of a substance that is required for 50% agonism in vivo, as further defined elsewhere herein.
  • EC 50 refers to the concentration of agonist that provokes a response halfway between the baseline and maximum response.
  • the terms "optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.
  • the term "subject” can be a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian.
  • the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent.
  • the term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered.
  • the subject is a mammal.
  • a patient refers to a subject afflicted with a disease or disorder.
  • patient includes human and veterinary subjects.
  • treatment refers to the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder.
  • This term includes active treatment, that is, treatment directed specifically toward the improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder.
  • this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder.
  • the term covers any treatment of a subject, including a mammal (e.g., a human), and includes: (i) preventing the disease from occurring in a subject that can be predisposed to the disease but has not yet been diagnosed as having it; (ii) inhibiting the disease, i.e., arresting its development; or (iii) relieving the disease, i.e., causing regression of the disease.
  • the subject is a mammal such as a primate, and, in a further aspect, the subject is a human.
  • subject also includes domesticated animals (e.g., cats, dogs, etc.), livestock (e.g., cattle, horses, pigs, sheep, goats, etc.), and laboratory animals (e.g., mouse, rabbit, rat, guinea pig, fruit fly, etc.).
  • domesticated animals e.g., cats, dogs, etc.
  • livestock e.g., cattle, horses, pigs, sheep, goats, etc.
  • laboratory animals e.g., mouse, rabbit, rat, guinea pig, fruit fly, etc.
  • prevent refers to precluding, averting, obviating, forestalling, stopping, or hindering something from happening, especially by advance action. It is understood that where reduce, inhibit or prevent are used herein, unless specifically indicated otherwise, the use of the other two words is also expressly disclosed.
  • diagnosis means having been subjected to a physical examination by a person of skill, for example, a physician, and found to have a condition that can be diagnosed or treated by the compounds, compositions, or methods disclosed herein.
  • administering refers to any method of providing a pharmaceutical preparation to a subject. Such methods are well known to those skilled in the art and include, but are not limited to, oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, intravaginal administration, ophthalmic administration, intraaural administration, intracerebral administration, rectal administration, sublingual administration, buccal administration, and parenteral administration, including injectable such as intravenous administration, intra-arterial administration, intramuscular administration, and subcutaneous administration. Administration can be continuous or intermittent.
  • a preparation can be administered therapeutically; that is, administered to treat an existing disease or condition.
  • a preparation can be administered prophylactically; that is, administered for prevention of a disease or condition.
  • the terms “effective amount” and “amount effective” refer to an amount that is sufficient to achieve the desired result or to have an effect on an undesired condition.
  • a “therapeutically effective amount” refers to an amount that is sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms, but is generally insufficient to cause adverse side effects.
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of a compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. If desired, the effective daily dose can be divided into multiple doses for purposes of administration.
  • compositions can contain such amounts or submultiples thereof to make up the daily dose.
  • the dosage can be adjusted by the individual physician in the event of any contraindications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products.
  • a preparation can be administered in a "prophylactically effective amount"; that is, an amount effective for prevention of a disease or condition.
  • dosage form means a pharmacologically active material in a medium, carrier, vehicle, or device suitable for administration to a subject.
  • a dosage forms can comprise inventive a disclosed compound, a product of a disclosed method of making, or a salt, solvate, or polymorph thereof, in combination with a pharmaceutically acceptable excipient, such as a preservative, buffer, saline, or phosphate buffered saline.
  • Dosage forms can be made using conventional pharmaceutical manufacturing and compounding techniques.
  • Dosage forms can comprise inorganic or organic buffers (e.g., sodium or potassium salts of phosphate, carbonate, acetate, or citrate) and pH adjustment agents (e.g ., hydrochloric acid, sodium or potassium hydroxide, salts of citrate or acetate, amino acids and their salts) antioxidants (e.g., ascorbic acid, alpha-tocopherol), surfactants (e.g., polysorbate 20, polysorbate 80, polyoxyethylene9-10 nonyl phenol, sodium desoxycholate), solution and/or cryo/lyo stabilizers (e.g., sucrose, lactose, mannitol, trehalose), osmotic adjustment agents (e.g., salts or sugars), antibacterial agents (e.g., benzoic acid, phenol, gentamicin), antifoaming agents (e.g., polydimethylsilozone), preservatives (e.g., thimerosal, 2-
  • a disorder associated with elevated TXNIP refers to a disease or condition marked by an increase as compared to the normal or non-diseased state.
  • terms such as “reduce” or “decrease” are used herein relative to treatment, in which they refer to normalizing the level or amount toward the control or normal state and may include a partial or complete normalization.
  • a disorder associated with elevated TXNIP and/or glucagon includes, for example, "diabetes and associated disorders" (e.g., Type 1 diabetes, Type 2 diabetes, gestational diabetes, impaired glucose tolerance or pre-diabetes, insulin resistance, hyperlipidemia, non-alcoholic fatty liver disease, complications of diabetes, including diabetes-related nephropathy, neuropathy, retinopathy, cardiomyopathy, and cardiovascular disease as well as pancreatic ⁇ -cell loss or pancreatic islet dysfunction, including dysregulation of insulin and/or glucagon production or secretion) or other disorders associated with endoplasmic reticulum stress and/or oxidative stress of the cell (including endogenous, ex vivo, or transplanted pancreatic islets).
  • hyperlipidemia and fatty liver disease may or may not be associated with diabetes or elevated TXNIP.
  • kit means a collection of at least two components constituting the kit. Together, the components constitute a functional unit for a given purpose. Individual member components may be physically packaged together or separately. For example, a kit comprising an instruction for using the kit may or may not physically include the instruction with other individual member components. Instead, the instruction can be supplied as a separate member component, either in a paper form or an electronic form which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation.
  • instruction(s) means documents describing relevant materials or methodologies pertaining to a kit. These materials may include any combination of the following: background information, list of components and their availability information (purchase information, etc.), brief or detailed protocols for using the kit, troubleshooting, references, technical support, and any other related documents. Instructions can be supplied with the kit or as a separate member component, either as a paper form or an electronic form which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation. Instructions can comprise one or multiple documents, and are meant to include future updates.
  • therapeutic agent include any synthetic or naturally occurring biologically active compound or composition of matter which, when administered to an organism (human or nonhuman animal), induces a desired pharmacologic, immunogenic, and/or physiologic effect by local and/or systemic action.
  • the term therefore encompasses those compounds or chemicals traditionally regarded as drugs, vaccines, and biopharmaceuticals including molecules such as proteins, peptides, hormones, nucleic acids, gene constructs and the like.
  • therapeutic agents include, without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of a disease or illness; substances that affect the structure or function of the body, or pro-drugs, which become biologically active or more active after they have been placed in a physiological environment.
  • the term "therapeutic agent” includes compounds or compositions for use in all of the major therapeutic areas including, but not limited to, adjuvants; anti-infectives such as antibiotics and antiviral agents; analgesics and analgesic combinations, anorexics, anti-inflammatory agents, anti-epileptics, local and general anesthetics, hypnotics, sedatives, antipsychotic agents, neuroleptic agents, antidepressants, anxiolytics, antagonists, neuron blocking agents, anticholinergic and cholinomimetic agents, antimuscarinic and muscarinic agents, antiadrenergics, antiarrhythmics, antihypertensive agents, hormones, and nutrients, antiarthritics, antiasthmatic agents, anticonvulsants, antihistamines, antinauseants, antineoplastics, antipruritics, antipyretics; antispasmodics, cardiovascular preparations (including calcium channel blockers, beta-blockers, an
  • the agent may be a biologically active agent used in medical, including veterinary, applications and in agriculture, such as with plants, as well as other areas.
  • therapeutic agent also includes without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of disease or illness; or substances which affect the structure or function of the body; or pro- drugs, which become biologically active or more active after they have been placed in a predetermined physiological environment.
  • pharmaceutically acceptable describes a material that is not biologically or otherwise undesirable, i . e ., without causing an unacceptable level of undesirable biological effects or interacting in a deleterious manner.
  • derivative refers to a compound having a structure derived from the structure of a parent compound (e.g., a compound disclosed herein) and whose structure is sufficiently similar to those disclosed herein and based upon that similarity, would be expected by one skilled in the art to exhibit the same or similar activities and utilities as the claimed compounds, or to induce, as a precursor, the same or similar activities and utilities as the claimed compounds.
  • exemplary derivatives include salts, esters, amides, salts of esters or amides, and N-oxides of a parent compound.
  • aqueous and nonaqueous carriers include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
  • These compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol, sorbic acid and the like. It can also be desirable to include isotonic agents such as sugars, sodium chloride and the like.
  • Prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents, such as aluminum monostearate and gelatin, which delay absorption.
  • Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide, poly(orthoesters) and poly(anhydrides). Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable media just prior to use.
  • Suitable inert carriers can include sugars such as lactose. Desirably, at least 95% by weight of the particles of the active ingredient have an effective particle size in the range of 0.01 to 10 micrometers.
  • the term "substituted" is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and aromatic and nonaromatic substituents of organic compounds.
  • Illustrative substituents include, for example, those described below.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms, such as nitrogen can have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
  • substitution or “substituted with” include the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e . g ., a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. It is also contemplated that, in certain aspects, unless expressly indicated to the contrary, individual substituents can be further optionally substituted ( i.e., further substituted or unsubstituted).
  • a 1 ,” “A 2 ,” “A 3 ,” and “A 4 " are used herein as generic symbols to represent various specific substituents. These symbols can be any substituent, not limited to those disclosed herein, and when they are defined to be certain substituents in one instance, they can, in another instance, be defined as some other substituents.
  • aliphatic or "aliphatic group,” as used herein, denotes a hydrocarbon moiety that may be straight-chain (i . e ., unbranched), branched, or cyclic (including fused, bridging, and spirofused polycyclic) and may be completely saturated or may contain one or more units of unsaturation, but which is not aromatic. Unless otherwise specified, aliphatic groups contain 1-20 carbon atoms. Aliphatic groups include, but are not limited to, linear or branched, alkyl, alkenyl, and alkynyl groups, and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
  • alkyl as used herein is a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, n -propyl, isopropyl, n- butyl, isobutyl, s -butyl, t -butyl, n -pentyl, isopentyl, s -pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like.
  • the alkyl group can be cyclic or acyclic.
  • the alkyl group can be branched or unbranched.
  • the alkyl group can also be substituted or unsubstituted.
  • the alkyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein.
  • a "lower alkyl” group is an alkyl group containing from one to six ( e.g., from one to four) carbon atoms.
  • alkyl group can also be a C1 alkyl, C1-C2 alkyl, C1-C3 alkyl, C1-C4 alkyl, C1-C5 alkyl, C1-C6 alkyl, C1-C7 alkyl, C1-C8 alkyl, C1-C9 alkyl, C1-C10 alkyl, and the like up to and including a C1-C24 alkyl.
  • alkyl is generally used to refer to both unsubstituted alkyl groups and substituted alkyl groups; however, substituted alkyl groups are also specifically referred to herein by identifying the specific substituent(s) on the alkyl group.
  • halogenated alkyl or “haloalkyl” specifically refers to an alkyl group that is substituted with one or more halide, e . g ., fluorine, chlorine, bromine, or iodine.
  • the term “monohaloalkyl” specifically refers to an alkyl group that is substituted with a single halide, e.g. fluorine, chlorine, bromine, or iodine.
  • polyhaloalkyl specifically refers to an alkyl group that is independently substituted with two or more halides, i.e. each halide substituent need not be the same halide as another halide substituent, nor do the multiple instances of a halide substituent need to be on the same carbon.
  • alkoxyalkyl specifically refers to an alkyl group that is substituted with one or more alkoxy groups, as described below.
  • aminoalkyl specifically refers to an alkyl group that is substituted with one or more amino groups.
  • hydroxyalkyl specifically refers to an alkyl group that is substituted with one or more hydroxy groups.
  • cycloalkyl refers to both unsubstituted and substituted cycloalkyl moieties
  • the substituted moieties can, in addition, be specifically identified herein; for example, a particular substituted cycloalkyl can be referred to as, e.g., an "alkylcycloalkyl.”
  • a substituted alkoxy can be specifically referred to as, e.g., a "halogenated alkoxy”
  • a particular substituted alkenyl can be, e.g., an "alkenylalcohol,” and the like.
  • cycloalkyl as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms.
  • examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and the like.
  • heterocycloalkyl is a type of cycloalkyl group as defined above, and is included within the meaning of the term “cycloalkyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus.
  • the cycloalkyl group and heterocycloalkyl group can be substituted or unsubstituted.
  • the cycloalkyl group and heterocycloalkyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein.
  • polyalkylene group as used herein is a group having two or more CH 2 groups linked to one another.
  • the polyalkylene group can be represented by the formula -(CH 2 ) a -, where "a" is an integer of from 2 to 500.
  • Alkoxy also includes polymers of alkoxy groups as just described; that is, an alkoxy can be a polyether such as -OA 1 -OA 2 or -OA 1 -(OA 2 ) a -OA 3 , where "a” is an integer of from 1 to 200 and A 1 , A 2 , and A 3 are alkyl and/or cycloalkyl groups.
  • alkenyl as used herein is a hydrocarbon group of from 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon double bond.
  • the alkenyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.
  • groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described here
  • Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, norbornenyl, and the like.
  • heterocycloalkenyl is a type of cycloalkenyl group as defined above, and is included within the meaning of the term “cycloalkenyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus.
  • the cycloalkenyl group and heterocycloalkenyl group can be substituted or unsubstituted.
  • the cycloalkenyl group and heterocycloalkenyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.
  • alkynyl as used herein is a hydrocarbon group of 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon triple bond.
  • the alkynyl group can be unsubstituted or substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.
  • cycloalkynyl as used herein is a non-aromatic carbon-based ring composed of at least seven carbon atoms and containing at least one carbon-carbon triple bound.
  • cycloalkynyl groups include, but are not limited to, cycloheptynyl, cyclooctynyl, cyclononynyl, and the like.
  • heterocycloalkynyl is a type of cycloalkenyl group as defined above, and is included within the meaning of the term “cycloalkynyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus.
  • the cycloalkynyl group and heterocycloalkynyl group can be substituted or unsubstituted.
  • the cycloalkynyl group and heterocycloalkynyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.
  • aromatic group refers to a ring structure having cyclic clouds of delocalized ⁇ electrons above and below the plane of the molecule, where the ⁇ clouds contain (4n+2) ⁇ electrons.
  • aromaticity is found in Morrison and Boyd, Organic Chemistry, (5th Ed., 1987), Chapter 13, entitled “Aromaticity,” pages 477-497 .
  • aromatic group is inclusive of both aryl and heteroaryl groups.
  • aryl as used herein is a group that contains any carbon-based aromatic group including, but not limited to, benzene, naphthalene, phenyl, biphenyl, anthracene, and the like.
  • the aryl group can be substituted or unsubstituted.
  • the aryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, -NH 2 , carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.
  • groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, -NH 2 , carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thi
  • biasing is a specific type of aryl group and is included in the definition of "aryl.”
  • the aryl group can be a single ring structure or comprise multiple ring structures that are either fused ring structures or attached via one or more bridging groups such as a carbon-carbon bond.
  • biaryl can be two aryl groups that are bound together via a fused ring structure, as in naphthalene, or are attached via one or more carbon-carbon bonds, as in biphenyl.
  • amine or “amino” as used herein are represented by the formula -NA 1 A 2 , where A 1 and A 2 can be, independently, hydrogen or alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • a specific example of amino is -NH 2 .
  • alkylamino as used herein is represented by the formula NH(-alkyl) where alkyl is a described herein.
  • Representative examples include, but are not limited to, methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, (sec-butyl)amino group, (tert-butyl)amino group, pentylamino group, isopentylamino group, (tert-pentyl)amino group, hexylamino group, and the like.
  • dialkylamino as used herein is represented by the formula -N(-alkyl) 2 where alkyl is a described herein.
  • Representative examples include, but are not limited to, dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, diisobutylamino group, di(sec-butyl)amino group, di(tert-butyl)amino group, dipentylamino group, diisopentylamino group, di(tert-pentyl)amino group, dihexylamino group, N-ethyl-N-methylamino group, N-methyl-N-propylamino group, N-ethyl-N-propylamino group and the like.
  • carboxylic acid as used herein is represented by the formula - C(O)OH.
  • esters as used herein is represented by the formula -OC(O)A 1 or -C(O)OA 1 , where A 1 can be alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • polystyrene resin as used herein is represented by the formula -(A 1 O(O)C-A 2 -C(O)O) a - or -(A 1 O(O)C-A 2 -OC(O)) a -, where A 1 and A 2 can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and "a” is an integer from 1 to 500.
  • Polyyester is as the term used to describe a group that is produced by the reaction between a compound having at least two carboxylic acid groups with a compound having at least two hydroxyl groups.
  • ether as used herein is represented by the formula A 1 OA 2 , where A 1 and A 2 can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein.
  • polyether as used herein is represented by the formula -(A 1 O-A 2 O) a -, where A 1 and A 2 can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and "a" is an integer of from 1 to 500.
  • Examples of polyether groups include polyethylene oxide, polypropylene oxide, and polybutylene oxide.
  • halo halogen
  • halide as used herein can be used interchangeably and refer to F, Cl, Br, or I.
  • pseudohalide pseudohalogen
  • pseudohalo pseudohalogen
  • pseudohalo pseudohalo
  • functional groups include, by way of example, cyano, thiocyanato, azido, trifluoromethyl, trifluoromethoxy, perfluoroalkyl, and perfluoroalkoxy groups.
  • heteroalkyl refers to an alkyl group containing at least one heteroatom. Suitable heteroatoms include, but are not limited to, O, N, Si, P and S, wherein the nitrogen, phosphorous and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. Heteroalkyls can be substituted as defined above for alkyl groups.
  • heteroaryl refers to an aromatic group that has at least one heteroatom incorporated within the ring of the aromatic group.
  • heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus, where N-oxides, sulfur oxides, and dioxides are permissible heteroatom substitutions.
  • the heteroaryl group can be substituted or unsubstituted.
  • the heteroaryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein.
  • Heteroaryl groups can be monocyclic, or alternatively fused ring systems. Heteroaryl groups include, but are not limited to, furyl, imidazolyl, pyrimidinyl, tetrazolyl, thienyl, pyridinyl, pyrrolyl, N- methylpyrrolyl, quinolinyl, isoquinolinyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridazinyl, pyrazinyl, benzofuranyl, benzodioxolyl, benzothiophenyl, indolyl, indazolyl, benzimidazolyl, imidazopyridinyl, pyrazolopyridinyl, and pyrazolopyrimidinyl.
  • heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, pyrazolyl, imidazolyl, benzo[d]oxazolyl, benzo[d]thiazolyl, quinolinyl, quinazolinyl, indazolyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazolyl, and pyrido[2,3-b]pyrazinyl.
  • heterocycle or “heterocyclyl,” as used herein can be used interchangeably and refer to single and multi-cyclic aromatic or non-aromatic ring systems in which at least one of the ring members is other than carbon.
  • the term is inclusive of, but not limited to, "heterocycloalkyl,” “heteroaryl,” “bicyclic heterocycle,” and “polycyclic heterocycle.”
  • Heterocycle includes pyridine, pyrimidine, furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole, imidazole, oxazole, including, 1,2,3-oxadiazole, 1,2,5-oxadiazole and 1,3,4-oxadiazole, thiadiazole, including, 1,2,3-thiadiazole, 1,2,5-thiadiazole, and 1,3,4-thiadiazole, triazole, including, 1,2,3-triazole
  • heterocyclyl group can also be a C2 heterocyclyl, C2-C3 heterocyclyl, C2-C4 heterocyclyl, C2-C5 heterocyclyl, C2-C6 heterocyclyl, C2-C7 heterocyclyl, C2-C8 heterocyclyl, C2-C9 heterocyclyl, C2-C10 heterocyclyl, C2-C11 heterocyclyl, and the like up to and including a C2-C18 heterocyclyl.
  • a C2 heterocyclyl comprises a group which has two carbon atoms and at least one heteroatom, including, but not limited to, aziridinyl, diazetidinyl, dihydrodiazetyl, oxiranyl, thiiranyl, and the like.
  • a C5 heterocyclyl comprises a group which has five carbon atoms and at least one heteroatom, including, but not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, diazepanyl, pyridinyl, and the like. It is understood that a heterocyclyl group may be bound either through a heteroatom in the ring, where chemically possible, or one of carbons comprising the heterocyclyl ring.
  • bicyclic heterocycle or "bicyclic heterocyclyl,” as used herein refers to a ring system in which at least one of the ring members is other than carbon.
  • Bicyclic heterocyclyl encompasses ring systems wherein an aromatic ring is fused with another aromatic ring, or wherein an aromatic ring is fused with a non-aromatic ring.
  • Bicyclic heterocyclyl encompasses ring systems wherein a benzene ring is fused to a 5- or a 6-membered ring containing 1, 2 or 3 ring heteroatoms or wherein a pyridine ring is fused to a 5- or a 6-membered ring containing 1, 2 or 3 ring heteroatoms.
  • Bicyclic heterocyclic groups include, but are not limited to, indolyl, indazolyl, pyrazolo[1,5-a]pyridinyl, benzofuranyl, quinolinyl, quinoxalinyl, 1,3-benzodioxolyl, 2,3-dihydro-1,4-benzodioxinyl, 3,4-dihydro-2H-chromenyl, 1H-pyrazolo[4,3-c]pyridin-3-yl; 1H-pyrrolo[3,2-b]pyridin-3-yl; and 1H-pyrazolo[3,2-b]pyridin-3-yl.
  • heterocycloalkyl refers to an aliphatic, partially unsaturated or fully saturated, 3- to 14-membered ring system, including single rings of 3 to 8 atoms and bi- and tricyclic ring systems.
  • the heterocycloalkyl ring-systems include one to four heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein a nitrogen and sulfur heteroatom optionally can be oxidized and a nitrogen heteroatom optionally can be substituted.
  • heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.
  • hydroxyl or "hydroxyl” as used herein is represented by the formula -OH.
  • ketone as used herein is represented by the formula A 1 C(O)A 2 , where A 1 and A 2 can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • nitro as used herein is represented by the formula -NO 2 .
  • nitrile or "cyano" as used herein is represented by the formula - CN.
  • sil as used herein is represented by the formula -SiA 1 A 2 A 3 , where A 1 , A 2 , and A 3 can be, independently, hydrogen or an alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • sulfo-oxo is represented by the formulas -S(O)A 1 , -S(O) 2 A 1 , -OS(O) 2 A 1 , or -OS(O) 2 OA 1 , where A 1 can be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • sulfonyl is used herein to refer to the sulfo-oxo group represented by the formula - S(O) 2 A 1 , where A 1 can be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • sulfone as used herein is represented by the formula A 1 S(O) 2 A 2 , where A 1 and A 2 can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • sulfoxide as used herein is represented by the formula A 1 S(O)A 2 , where A 1 and A 2 can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • thiol as used herein is represented by the formula -SH.
  • R 1 ,” “R 2 ,” “R 3 ,” “R n ,” where n is an integer, as used herein can, independently, possess one or more of the groups listed above.
  • R 1 is a straight chain alkyl group
  • one of the hydrogen atoms of the alkyl group can optionally be substituted with a hydroxyl group, an alkoxy group, an alkyl group, a halide, and the like.
  • a first group can be incorporated within second group or, alternatively, the first group can be pendant ( i . e ., attached) to the second group.
  • an alkyl group comprising an amino group the amino group can be incorporated within the backbone of the alkyl group.
  • the amino group can be attached to the backbone of the alkyl group.
  • the nature of the group(s) that is (are) selected will determine if the first group is embedded or attached to the second group.
  • compounds of the invention may contain "optionally substituted” moieties.
  • substituted whether preceded by the term “optionally” or not, means that one or more hydrogen of the designated moiety are replaced with a suitable substituent.
  • an "optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds.
  • individual substituents can be further optionally substituted (i .e. , further substituted or unsubstituted).
  • stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain aspects, their recovery, purification, and use for one or more of the purposes disclosed herein.
  • Suitable monovalent substituents on R° are independently halogen, -(CH 2 ) 0-2 R • , -(haloR • ), -(CH 2 ) 0-2 OH, -(CH 2 ) 0-2 OR • , -(CH 2 ) 0-2 CH(OR • ) 2 ; -O(haloR'), -CN, -N 3 , -(CH 2 ) 0-2 C(O)R • , -(CH 2 ) 0-2 C(O)OH, -(CH 2 ) 0-2 C(O)OR • , -(CH 2 ) 0-2 SR • , -(CH 2 ) 0-2 SH, -(CH 2 ) 0-2 NH 2 , -(CH 2 ) 0-2 NHR • , -(CH 2 ) 0-2 NR • 2 ,
  • Suitable divalent substituents that are bound to vicinal substitutable carbons of an "optionally substituted” group include: -O(CR ⁇ 2 ) 2-3 O-, wherein each independent occurrence of R ⁇ is selected from hydrogen, C 1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on the aliphatic group of R ⁇ include halogen, -R • , -(haloR • ), -OH, -OR • , -O(haloR • ), -CN, -C(O)OH, -C(O)OR*, -NH 2 , -NHR • , -NR • 2 , or - NO 2 , wherein each R • is unsubstituted or where preceded by "halo" is substituted only with one or more halogens, and is independently C 1-4 aliphatic, -CH 2 Ph, -O(CH 2 ) 0-1 Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include -R ⁇ , -NR ⁇ 2 , -C(O)R ⁇ , -C(O)OR ⁇ , -C(O)C(O)R ⁇ , -C(O)CH 2 C(O)R ⁇ , - S(O) 2 R ⁇ , -S(O) 2 NR ⁇ 2 , -C(S)NR ⁇ 2 , -C(NH)NR ⁇ 2 , or -N(R ⁇ )S(O) 2 R ⁇ ; wherein each R ⁇ is independently hydrogen, C 1-6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrence
  • Suitable substituents on the aliphatic group of R ⁇ are independently halogen, - R • , -(haloR • ), -OH, -OR • , -O(haloR'), -CN, -C(O)OH, -C(O)OR*, -NH 2 , -NHR • , -NR • 2 , or -NO 2 , wherein each R' is unsubstituted or where preceded by "halo" is substituted only with one or more halogens, and is independently C 1-4 aliphatic, -CH 2 Ph, -O(CH 2 ) 0-1 Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • leaving group refers to an atom (or a group of atoms) with electron withdrawing ability that can be displaced as a stable species, taking with it the bonding electrons.
  • suitable leaving groups include halides and sulfonate esters, including, but not limited to, triflate, mesylate, tosylate, and brosylate.
  • hydrolysable group and “hydrolysable moiety” refer to a functional group capable of undergoing hydrolysis, e.g., under basic or acidic conditions.
  • hydrolysable residues include, without limitation, acid halides, activated carboxylic acids, and various protecting groups known in the art (see, for example, “ Greene's Protective Groups in Organic Synthesis,” P. G. M. Wuts, Wiley, 2014 ).
  • organic residue defines a carbon containing residue, i.e., a residue comprising at least one carbon atom, and includes but is not limited to the carbon-containing groups, residues, or radicals defined hereinabove.
  • Organic residues can contain various heteroatoms, or be bonded to another molecule through a heteroatom, including oxygen, nitrogen, sulfur, phosphorus, or the like. Examples of organic residues include but are not limited alkyl or substituted alkyls, alkoxy or substituted alkoxy, mono or di-substituted amino, amide groups, etc.
  • Organic residues can preferably comprise 1 to 18 carbon atoms, 1 to 15, carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms.
  • an organic residue can comprise 2 to 18 carbon atoms, 2 to 15, carbon atoms, 2 to 12 carbon atoms, 2 to 8 carbon atoms, 2 to 4 carbon atoms, or 2 to 4 carbon atoms.
  • a radical in a particular compound has the structure: regardless of whether thiazolidinedione is used to prepare the compound.
  • the radical for example an alkyl
  • the radical can be further modified (i.e., substituted alkyl) by having bonded thereto one or more "substituent radicals.”
  • the number of atoms in a given radical is not critical to the present invention unless it is indicated to the contrary elsewhere herein.
  • Organic radicals contain one or more carbon atoms.
  • An organic radical can have, for example, 1-26 carbon atoms, 1-18 carbon atoms, 1-12 carbon atoms, 1-8 carbon atoms, 1-6 carbon atoms, or 1-4 carbon atoms.
  • an organic radical can have 2-26 carbon atoms, 2-18 carbon atoms, 2-12 carbon atoms, 2-8 carbon atoms, 2-6 carbon atoms, or 2-4 carbon atoms.
  • Organic radicals often have hydrogen bound to at least some of the carbon atoms of the organic radical.
  • an organic radical that comprises no inorganic atoms is a 5, 6, 7, 8-tetrahydro-2-naphthyl radical.
  • an organic radical can contain 1-10 inorganic heteroatoms bound thereto or therein, including halogens, oxygen, sulfur, nitrogen, phosphorus, and the like.
  • organic radicals include but are not limited to an alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, mono-substituted amino, di-substituted amino, acyloxy, cyano, carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide, substituted dialkylcarboxamide, alkylsulfonyl, alkylsulfinyl, thioalkyl, thiohaloalkyl, alkoxy, substituted alkoxy, haloalkyl, haloalkoxy, aryl, substituted aryl, heteroaryl, heterocyclic, or substituted heterocyclic radicals, wherein the terms are defined elsewhere herein.
  • organic radicals that include heteroatoms include alkoxy radicals, trifluoromethoxy radicals, acetoxy radicals, dimethylamino radicals and the like.
  • a formula with chemical bonds shown only as solid lines and not as wedges or dashed lines contemplates each possible isomer, e.g., each enantiomer and diastereomer, and a mixture of isomers, such as a racemic or scalemic mixture.
  • Compounds described herein can contain one or more asymmetric centers and, thus, potentially give rise to diastereomers and optical isomers.
  • the present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof. Mixtures of stereoisomers, as well as isolated specific stereoisomers, are also included.
  • the products of such procedures can be a mixture of stereoisomers.
  • a specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture.
  • a 50:50 mixture of enantiomers is referred to as a racemic mixture.
  • Many of the compounds described herein can have one or more chiral centers and therefore can exist in different enantiomeric forms. If desired, a chiral carbon can be designated with an asterisk (*). When bonds to the chiral carbon are depicted as straight lines in the disclosed formulas, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence both enantiomers and mixtures thereof, are embraced within the formula.
  • one of the bonds to the chiral carbon can be depicted as a wedge (bonds to atoms above the plane) and the other can be depicted as a series or wedge of short parallel lines is (bonds to atoms below the plane).
  • the Cahn-Ingold-Prelog system can be used to assign the (R) or (S) configuration to a chiral carbon.
  • a disclosed compound includes both enantiomers and mixtures of enantiomers, such as the specific 50:50 mixture referred to as a racemic mixture.
  • the enantiomers can be resolved by methods known to those skilled in the art, such as formation of diastereoisomeric salts which may be separated, for example, by crystallization (see, CRC Handbook of Optical Resolutions via Diastereomeric Salt Formation by David Kozma (CRC Press, 2001 )); formation of diastereoisomeric derivatives or complexes which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic esterification; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support for example silica with a bound chiral ligand or in the presence of a chiral solvent.
  • a further step can liberate the desired enantiomeric form.
  • specific enantiomers can be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer into the other by asymmetric transformation.
  • Designation of a specific absolute configuration at a chiral carbon in a disclosed compound is understood to mean that the designated enantiomeric form of the compounds can be provided in enantiomeric excess (e.e.).
  • Enantiomeric excess is the presence of a particular enantiomer at greater than 50%, for example, greater than 60%, greater than 70%, greater than 75%, greater than 80%, greater than 85%, greater than 90%, greater than 95%, greater than 98%, or greater than 99%.
  • the designated enantiomer is substantially free from the other enantiomer.
  • the "R” forms of the compounds can be substantially free from the "S” forms of the compounds and are, thus, in enantiomeric excess of the "S” forms.
  • "S” forms of the compounds can be substantially free of “R” forms of the compounds and are, thus, in enantiomeric excess of the "R” forms.
  • a disclosed compound When a disclosed compound has two or more chiral carbons, it can have more than two optical isomers and can exist in diastereoisomeric forms. For example, when there are two chiral carbons, the compound can have up to four optical isomers and two pairs of enantiomers ((S,S)/(R,R) and (R,S)/(S,R)).
  • the pairs of enantiomers e.g., (S,S)/(R,R)
  • the stereoisomers that are not mirror-images e.g., (S,S) and (R,S) are diastereomers.
  • diastereoisomeric pairs can be separated by methods known to those skilled in the art, for example chromatography or crystallization and the individual enantiomers within each pair may be separated as described above. Unless otherwise specifically excluded, a disclosed compound includes each diastereoisomer of such compounds and mixtures thereof.
  • the compounds according to this disclosure may form prodrugs at hydroxyl or amino functionalities using alkoxy, amino acids, etc., groups as the prodrug forming moieties.
  • the hydroxymethyl position may form mono-, di- or triphosphates and again these phosphates can form prodrugs.
  • Preparations of such prodrug derivatives are discussed in various literature sources (examples are: Alexander et al., J. Med. Chem. 1988, 31, 318 ; Aligas-Martin et al., PCT WO 2000/041531 , p. 30).
  • the nitrogen function converted in preparing these derivatives is one (or more) of the nitrogen atoms of a compound of the disclosure.
  • “Derivatives” of the compounds disclosed herein are pharmaceutically acceptable salts, prodrugs, deuterated forms, radio-actively labeled forms, isomers, solvates and combinations thereof.
  • the “combinations” mentioned in this context are refer to derivatives falling within at least two of the groups: pharmaceutically acceptable salts, prodrugs, deuterated forms, radio-actively labeled forms, isomers, and solvates.
  • Examples of radio-actively labeled forms include compounds labeled with tritium, phosphorous-32, iodine-129, carbon-11, fluorine-18, and the like.
  • Compounds described herein comprise atoms in both their natural isotopic abundance and in non-natural abundance.
  • the disclosed compounds can be isotopically-labeled or isotopically-substituted compounds identical to those described, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 35 S, 18 F and 36 Cl, respectively.
  • Compounds further comprise prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms.
  • Certain isotopically-labeled compounds of the present invention for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
  • isotopically labeled compounds of the present invention and prodrugs thereof can generally be prepared by carrying out the procedures below, by substituting a readily available isotopically labeled reagent for a non- isotopically labeled reagent.
  • the compounds described in the invention can be present as a solvate.
  • the solvent used to prepare the solvate is an aqueous solution, and the solvate is then often referred to as a hydrate.
  • the compounds can be present as a hydrate, which can be obtained, for example, by crystallization from a solvent or from aqueous solution.
  • one, two, three or any arbitrary number of solvent or water molecules can combine with the compounds according to the invention to form solvates and hydrates.
  • the invention includes all such possible solvates.
  • co-crystal means a physical association of two or more molecules which owe their stability through non-covalent interaction.
  • One or more components of this molecular complex provide a stable framework in the crystalline lattice.
  • the guest molecules are incorporated in the crystalline lattice as anhydrates or solvates, see e.g. " Crystal Engineering of the Composition of Pharmaceutical Phases. Do Pharmaceutical Co-crystals Represent a New Path to Improved Medicines?" Almarasson, O., et al., The Royal Society of Chemistry, 1889-1896, 2004 .
  • Examples of co-crystals include p-toluenesulfonic acid and benzenesulfonic acid.
  • ketones with an ⁇ -hydrogen can exist in an equilibrium of the keto form and the enol form.
  • amides with an N-hydrogen can exist in an equilibrium of the amide form and the imidic acid form.
  • pyrazoles can exist in two tautomeric forms, N 1 -unsubstituted, 3-A 3 and N 1 -unsubstituted, 5-A 3 as shown below. Unless stated to the contrary, the invention includes all such possible tautomers.
  • polymorphic forms It is known that chemical substances form solids which are present in different states of order which are termed polymorphic forms or modifications.
  • the different modifications of a polymorphic substance can differ greatly in their physical properties.
  • the compounds according to the invention can be present in different polymorphic forms, with it being possible for particular modifications to be metastable. Unless stated to the contrary, the invention includes all such possible polymorphic forms.
  • a structure of a compound can be represented by a formula: which is understood to be equivalent to a formula: wherein n is typically an integer. That is, R n is understood to represent five independent substituents, R n (a) , R n (b) , R n (c) , R n (d) , R n (e) .
  • independent substituents it is meant that each R substituent can be independently defined. For example, if in one instance R n (a) is halogen, then R n (b) is not necessarily halogen in that instance.
  • Certain materials, compounds, compositions, and components disclosed herein can be obtained commercially or readily synthesized using techniques generally known to those of skill in the art.
  • the starting materials and reagents used in preparing the disclosed compounds and compositions are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Acros Organics (Morris Plains, N.J.), Strem Chemicals (Newburyport, MA), Fisher Scientific (Pittsburgh, Pa.), or Sigma (St.
  • compositions of the invention Disclosed are the components to be used to prepare the compositions of the invention as well as the compositions themselves to be used within the methods disclosed herein.
  • these and other materials are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutation of these compounds cannot be explicitly disclosed, each is specifically contemplated and described herein. For example, if a particular compound is disclosed and discussed and a number of modifications that can be made to a number of molecules including the compounds are discussed, specifically contemplated is each and every combination and permutation of the compound and the modifications that are possible unless specifically indicated to the contrary.
  • compositions disclosed herein have certain functions. Disclosed herein are certain structural requirements for performing the disclosed functions, and it is understood that there are a variety of structures that can perform the same function that are related to the disclosed structures, and that these structures will typically achieve the same result.
  • the compounds and compositions disclosed herein are useful for treating, preventing, ameliorating, controlling or reducing the risk of a variety of disorders associated with elevated TXNIP expression and/or elevated glucagon levels, including, for example, diabetes or diabetes related disorders.
  • methods of treating or preventing a disorder associated with elevated TXNIP in a subject comprising the step of administering to the subject an effective amount of at least one disclosed compound or a pharmaceutically acceptable salt thereof.
  • an effective amount of the at least one compound or pharmaceutically acceptable salt thereof may work by one or more mechanisms, for example, by directly or indirectly inhibiting TXNIP expression and signalingand/or by reducing circulating glucagon levels.
  • the compo unds or compositions as disclosed herein do not block calcium channels.
  • the clinical outcome optionally includes improved blood glucose control, lower hepatic glucose production, lower serum glucagon levels, and/or signs of higher insulin production as compared to the absence of at least one compound or pharmaceutically acceptable salt thereof.
  • n is 0, 1, or 2; wherein p is 0, 1, 2, 3, or 4; wherein q is 0 or 1; wherein R 1 is -NH 2 , - OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, -(C1-C4 alkyl)(C1-C4 alkoxy), -(C1-C4 alkyl)CO 2 H, or Cy 1 ; wherein Cy 1 , when present, is C3-C6 cycloalky
  • Also disclosed are methods for treating or preventing a disorder associated with elevated TXNIP and/or glucagon in a mammal comprising the step of administering to the mammal a therapeutically effective amount of at least one compound having a structure represented by a formula:
  • the disorder associated with elevated TXNIP and/or glucagon is a disorder affecting regulation of hepatic glucose production.
  • the disorder associated with elevated TXNIP and/or glucagon is diabetes or a diabetes related disorder.
  • the diabetes is selected from Type I diabetes, Type II diabetes, and gestational diabetes.
  • the diabetes is Type I diabetes.
  • the diabetes is Type II diabetes.
  • the diabetes is gestational diabetes.
  • the disclosed compounds can be used in combination with one or more other drugs in the treatment, prevention, control, amelioration, or reduction of risk of disorders associated with elevated TXNIP and/or elevated glucagon levels for which disclosed compounds or the other drugs can have utility, where the combination of the drugs together are safer or more effective than either drug alone.
  • Such other drug(s) can be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the present invention.
  • a pharmaceutical composition in unit dosage form containing such other drugs and a disclosed compound is preferred.
  • the combination therapy can also include therapies in which a disclosed compound and one or more other drugs are administered on different overlapping schedules.
  • the disclosed compounds and the other active ingredients can be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions include those that contain one or more other active ingredients, in addition to a compound of the present invention.
  • the compound exhibits inhibition of TXNIP expression or function and/or lowers glucagon levels. In a further aspect, the compound exhibits inhibition of TXNIP expression or function and/or lowers glucagon levels with an IC 50 of from about 0.001 ⁇ M to about 25 ⁇ M. In a still further aspect, the compound exhibits inhibition of TXNIP expression or function and/or lowers glucagon levels with an IC 50 of from about 0.001 ⁇ M to about 15 ⁇ M. In yet a further aspect, the compound exhibits inhibition of TXNIP expression or function and/or lowers glucagon levels with an IC 50 of from about 0.001 ⁇ M to about 10 ⁇ M.
  • the compound exhibits inhibition of TXNIP expression or function and/or lowers glucagon with an IC 50 of from about 0.001 ⁇ M to about 5 ⁇ M. In a still further aspect, the compound exhibits inhibition of TXNIP expression or function and/or lowers glucagon levels with an IC 50 of from about 0.001 ⁇ M to about 1 ⁇ M. In yet a further aspect, the compound exhibits inhibition of TXNIP expression or function and/or lowers glucagon with an IC 50 of from about 0.001 ⁇ M to about 0.5 ⁇ M.
  • the compound exhibits inhibition of TXNIP expression or function and/or lowers glucagon with an IC 50 of from about 0.001 ⁇ M to about 0.1 ⁇ M. In a still further aspect, the compound exhibits inhibition of TXNIP expression or function and/or lowers glucagon levels with an IC 50 of from about 0.001 ⁇ M to about 0.05 ⁇ M. In yet a further aspect, the compound exhibits inhibition of TXNIP expression or function and/or lowers glucagon levels with an IC 50 of from about 0.001 ⁇ M to about 0.01 ⁇ M.
  • the compound exhibits inhibition of TXNIP expression or function and/or lowers glucagon levels with an IC 50 of from about 0.001 ⁇ M to about 0.005 ⁇ M. In a still further aspect, the compound exhibits inhibition of TXNIP expression or function and/or lowers glucagon levels with an IC 50 of from about 0.005 ⁇ M to about 25 ⁇ M. In yet a further aspect, the compound exhibits inhibition of TXNIP expression or function and/or lowers glucagon levels with an IC 50 of from about 0.01 ⁇ M to about 25 ⁇ M.
  • the compound exhibits inhibition of TXNIP expression or function and/or lowers glucagon levels with an IC 50 of from about 0.05 ⁇ M to about 25 ⁇ M. In a still further aspect, the compound exhibits inhibition of TXNIP expression or function and/or lowers glucagon levels with a IC 50 of from about 0.1 ⁇ M to about 25 ⁇ M. In yet a further aspect, the compound exhibits inhibition of TXNIP expression or function and/or lowers glucagon levels with an IC 50 of from about 0.5 ⁇ M to about 25 ⁇ M.
  • the compound exhibits inhibition of TXNIP expression or function and/or lowers glucagon levels with an IC 50 of from about 1 ⁇ M to about 25 ⁇ M. In a still further aspect, the compound exhibits inhibition of TXNIP expression or function and/or lowers glucagon levels with an IC 50 of from about 5 ⁇ M to about 25 ⁇ M. In yet a further aspect, the compound exhibits inhibition of TXNIP expression or function and/or lowers glucagon levels with an IC 50 of from about 10 ⁇ M to about 25 ⁇ M. In an even further aspect, the compound exhibits inhibition of TXNIP expression or function and/or lowers glucagon levels with a IC 50 of from about 15 ⁇ M to about 25 ⁇ M.
  • the subject is a mammal.
  • the mammal is a human.
  • the subject has been diagnosed with a need for treatment of the disorder associated with elevated TXNIP and/or glucagon prior to the administering step.
  • the subject is at risk for developing the disorder prior to the administering step.
  • the effective amount is a therapeutically effective amount. In a still further aspect, the effective amount is a prophylactically effective amount.
  • the method further comprises identifying a subject at risk for developing the disorder prior to the administering step.
  • the method further comprises the step of identifying a subject in need of treatment of a disorder associated with elevated TXNIP and/or glucagon.
  • Described herein are methods for preventing or treating hyperlipidemia and/or fatty liver disease (e.g., nonalcoholic fatty liver disease) in a subject.
  • the methods comprise administering to the subject an effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt thereof.
  • the hyperlipidemia and/or fatty liver disease is optionally in the presence or absence of elevated TXNIP or in the presence or absence of diabetes or other diabetes related disorders.
  • the disclosed compounds or pharmaceutical salts are effective in treating hyperlipidemia or fatty liver disease even without an apparent need for reduction of TXNIP.
  • the disclosed methods include administering to the mammal a therapeutically effective amount of at least one pharmaceutical composition or compound as described herein.
  • the disclosed compounds can be used in combination with one or more other drugs in the treatment, prevention, control, amelioration, or reduction of risk of hyperlipidemia and/or fatty liver disease, where the combination of the drugs together are safer or more effective than either drug alone.
  • Such other drug(s) can be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a disclosed compound, as described above.
  • the subject is a mammal.
  • the mammal is a human.
  • the subject has been diagnosed with a need for treatment of hyperlipidemia and/or fatty liver disease prior to the administering step.
  • the subject is at risk for developing hyperlipidemia and/or fatty liver disease prior to the administering step.
  • the effective amount is a therapeutically effective amount. In a still further aspect, the effective amount is a prophylactically effective amount.
  • the method further comprises identifying a subject at risk for developing hyperlipidemia and/or fatty liver disease prior to the administering step.
  • disclosed are methods of inhibiting TXNIP expression or function or lowering hepatic glucose production in a subject comprising the step of administering to the subject an effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt thereof.
  • the method of inhibiting TXNIP expression or function or lowering hepatic glucose production is optionally selected from the group consisting of diabetes, diabetes related disorders, hyperlipidemia, and fatty liver disease.
  • n is 0, 1, or 2; wherein p is 0, 1, 2, 3, or 4; wherein q is 0 or 1; wherein R 1 is -NH 2 , - OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, -(C1-C4 alkyl)(C1-C4 alkoxy), -(C1-C4 alkyl)CO 2 H, or Cy 1 ; wherein Cy 1 , when present, is C3-C6 cycloalkyl, C2-C
  • Also disclosed are methods for inhibiting TXNIP expression and/or lowering hepatic glucose production in a mammal comprising the step of administering to the mammal an effective amount of at least one compound having a structure represented by a formula: wherein n is 0, 1, or 2; wherein each of p and q is independently 0 or 1; wherein R 1 is -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, or Cy 1 ; wherein Cy 1 , when present, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C
  • inhibiting TXNIP expression and/or lowering hepatic glucose production in the mammal treats diabetes in the mammal.
  • the subject has been diagnosed with a disorder associated with elevated TXNIP and/or glucagon prior to the administering step.
  • the subject has been diagnosed with diabetes prior to the administering step.
  • the method further comprises the step of identifying a subject in need of treatment of a disorder of hepatic glucose regulation dysfunction.
  • the method further comprises the step of identifying a subject in need of treatment of diabetes.
  • the subject has been diagnosed with a need for inhibition of TXNIP and/or lowering hepatic glucose production prior to the administering step.
  • the subject has been diagnosed with a need for treatment of a disorder associated with elevated TXNIP and/or glucagon prior to the administering step.
  • the method further comprises the step of identifying a subject in need of treatment.
  • the disorder associated with elevated TXNIP and/or glucagon is a disorder of hepatic glucose regulation dysfunction.
  • the disorder is diabetes.
  • the diabetes is selected from Type I diabetes, Type II diabetes, gestational diabetes, or pre-diabetes/impaired glucose tolerance or a diabetes related disorder.
  • the diabetes is Type I diabetes.
  • the diabetes is Type II diabetes.
  • the diabetes is gestational diabetes or pre-diabetes/impaired glucose tolerance.
  • the compound exhibits inhibition of TXNIP and/or lowers glucagon levels with an IC 50 of from about 0.001 ⁇ M to about 25 ⁇ M. In a still further aspect, the compound exhibits inhibition of TXNIP and/or lowers glucagon with an IC 50 of from about 0.001 ⁇ M to about 15 ⁇ M. In yet a further aspect, the compound exhibits inhibition of TXNIP and/or lowers glucagon levels with an IC 50 of from about 0.001 ⁇ M to about 10 ⁇ M. In an even further aspect, the compound exhibits inhibition of TXNIP and/or lowers glucagon levels with an IC 50 of from about 0.001 ⁇ M to about 5 ⁇ M.
  • the compound exhibits inhibition of TXNIP and/or lowers glucagon levels with an IC 50 of from about 0.001 ⁇ M to about 1 ⁇ M. In yet a further aspect, the compound exhibits inhibition of TXNIP and/or lowers glucagon levels with an IC 50 of from about 0.001 ⁇ M to about 0.5 ⁇ M. In an even further aspect, the compound exhibits inhibition of TXNIP and/or lowers glucagon levels with an IC 50 of from about 0.001 ⁇ M to about 0.1 ⁇ M.
  • the compound exhibits inhibition of TXNIP and/or lowers glucagon levels with an IC 50 of from about 0.001 ⁇ M to about 0.05 ⁇ M. In yet a further aspect, the compound exhibits inhibition of TXNIP and/or lowers glucagon levels with an IC 50 of from about 0.001 ⁇ M to about 0.01 ⁇ M. In an even further aspect, the compound exhibits inhibition of TXNIP and/or lowers glucagon levels with an IC 50 of from about 0.001 ⁇ M to about 0.005 ⁇ M.
  • the compound exhibits inhibition of TXNIP and/or lowers glucagon levels with an IC 50 of from about 0.005 ⁇ M to about 25 ⁇ M. In yet a further aspect, the compound exhibits inhibition of TXNIP and/or lowers glucagon levels with an IC 50 of from about 0.01 ⁇ M to about 25 ⁇ M. In an even further aspect, the compound exhibits inhibition of TXNIP and/or lowers glucagon levels with an IC 50 of from about 0.05 ⁇ M to about 25 ⁇ M. In a still further aspect, the compound exhibits inhibition of TXNIP and/or lowers glucagon levels with an IC 50 of from about 0.1 ⁇ M to about 25 ⁇ M.
  • the compound exhibits inhibition of TXNIP and/or lowers glucagon levels with an IC 50 of from about 0.5 ⁇ M to about 25 ⁇ M. In an even further aspect, the compound exhibits inhibition of TXNIP and/or lowers glucagon levels with an IC 50 of from about 1 ⁇ M to about 25 ⁇ M. In a still further aspect, the compound exhibits inhibition of TXNIP and/or lowers glucagon levels with an IC 50 of from about 5 ⁇ M to about 25 ⁇ M. In yet a further aspect, the compound exhibits inhibition of TXNIP and/or lowers glucagon levels with an IC 50 of from about 10 ⁇ M to about 25 ⁇ M. In an even further aspect, the compound exhibits inhibition of TXNIP and/or lowers glucagon levels with an IC 50 of from about 15 ⁇ M to about 25 ⁇ M.
  • the subject is a mammal.
  • the mammal is a human.
  • the effective amount is a therapeutically effective amount. In a still further aspect, the effective amount is a prophylactically effective amount.
  • the method includes culturing cells stably transfected with an exogenous TXNIP promoter (e.g., a human TXNIP promoter) in a first culture medium containing a low level of glucose; then culturing a first subset of the cells in a second culture medium containing a high level of glucose and a second subset of the cells in a third culture medium containing a high level of glucose and an agent to be tested; and comparing the level of TXNIP promoter activity in the first subset of cells with the level of TXNIP promoter activity in the second subset of cells.
  • a lower level of TXNIP promoter activity in the second subset of cells as compared to the first subset of cells indicates the agent is an inhibitor of glucose-induced TXNIP expression.
  • culturing in a high level of glucose or a low level of glucose refers to the levels higher or lower than the optimal level of glucose for culture of the specific cell type.
  • the optimal glucose level for culturing INS-1 cells is about 11.1 mM.
  • a low level of glucose is less than 11.1 (e.g., 3-10 mM, 5-7mM, or more specifically about 5mM)
  • a high level of glucose is higher than 11.1 (e.g., 12-30 mM, 15-25 mM, or, more specifically, about 25mM).
  • the method further includes determining the identified inhibitor of glucose-induced TXNIP expression is a selective inhibitor of TXNIP expression rather than a general transcriptional inhibitor by testing its effects on the promoter of a non-TXNIP gene (e.g., a CMV promoter) and/or treating a cell co-transfected with a first and second exogenous promoter with the identified inhibitor of glucose-induced TXNIP expression, wherein the first exogenous promoter is a TXNIP promoter and the second exogenous promoter promotes expression of a control non-TXNIP gene (e.g., a pRLTK promoter), and detecting the level of promoter activity of the TXNIP and the non-TXNIP gene.
  • a control non-TXNIP gene e.g., a pRLTK promoter
  • Detecting a reduction in the level of the TXNIP promoter activity without reduction in the level of the non-TXNIP gene control promoter as compared to a control cell without contact with the inhibitor of glucose-induced TXNIP determines that the identified inhibitor of glucose-induced TXNIP expression is not a general transcriptional inhibitor.
  • the method further comprises screening the inhibitor of glucose-induced TXNIP by contacting a primary culture of cells (e.g., isolated islets or cardiomyocytes) with the agent in the presence of low and high glucose and/or by administering the inhibitor to a subject with diabetes.
  • a primary culture of cells e.g., isolated islets or cardiomyocytes
  • compositions comprising a disclosed compound, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one compound having a structure represented by a formula: wherein n is 0, 1, or 2; wherein p is 1, 2, 3, or 4; wherein q is 0 or 1; wherein R 1 is -NH 2 , - OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, -(C1-C4 alkyl)(C1-C4 alkoxy), -(C1-C4 alkyl)CO 2 H, or Cy 1 ; wherein Cy 1 , when present, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen,
  • compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one compound having a structure represented by a formula: wherein n is 0, 1, or 2; wherein q is 0 or 1; wherein R 1 is -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, -(C1-C4 alkyl)(C1-C4 alkoxy), -(C1-C4 alkyl)CO 2 H, or Cy 1 ; wherein Cy 1 , when present, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -NH 2 , -OH, C1
  • compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one compound having a structure represented by a formula selected from: wherein n is 0, 1, or 2; wherein p is 0, 1, 2, 3, or 4; wherein q is 0 or 1; wherein R 1 is -NH 2 , - OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, -(C1-C4 alkyl)(C1-C4 alkoxy), -(C1-C4 alkyl)CO 2 H, or Cy 1 ; wherein Cy 1 , when present, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen,
  • compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one compound having a structure represented by a formula: wherein n is 0, 1, or 2; wherein q is 0 or 1; wherein R 1 is -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, or Cy 1 ; wherein Cy 1 , when present, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)(C1
  • compositions comprising pharmaceutically acceptable carrier and a therapeutically effective amount of at least one compound having a structure represented by a formula: wherein n is 0, 1, or 2; wherein q is 0 or 1; wherein R 1 is -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, or Cy 1 ; wherein Cy 1 , when present, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)(C1-C
  • the compounds and compositions of the invention can be administered in pharmaceutical compositions, which are formulated according to the intended method of administration.
  • the compounds and compositions described herein can be formulated in a conventional manner using one or more physiologically acceptable carriers or excipients.
  • a pharmaceutical composition can be formulated for local or systemic administration, e.g., administration by drops or injection into the ear, insufflation (such as into the ear), intravenous, topical, or oral administration.
  • the pharmaceutical compositions for administration is dependent on the mode of administration and can readily be determined by one of ordinary skill in the art.
  • the pharmaceutical composition is sterile or sterilizable.
  • the therapeutic compositions featured in the invention can contain carriers or excipients, many of which are known to skilled artisans. Excipients that can be used include buffers (for example, citrate buffer, phosphate buffer, acetate buffer, and bicarbonate buffer), amino acids, urea, alcohols, ascorbic acid, phospholipids, polypeptides (for example, serum albumin), EDTA, sodium chloride, liposomes, mannitol, sorbitol, water, and glycerol.
  • nucleic acids, polypeptides, small molecules, and other modulatory compounds featured in the invention can be administered by any standard route of administration.
  • administration can be parenteral, intravenous, subcutaneous, or oral.
  • a modulatory compound can be formulated in various ways, according to the corresponding route of administration.
  • liquid solutions can be made for administration by drops into the ear, for injection, or for ingestion; gels or powders can be made for ingestion or topical application. Methods for making such formulations are well known and can be found in, for example, Remington's Pharmaceutical Sciences, 18th Ed., Gennaro, ed., Mack Publishing Co., Easton, PA 1990 .
  • the disclosed pharmaceutical compositions comprise the disclosed compounds (including pharmaceutically acceptable salt(s) thereof) as an active ingredient, a pharmaceutically acceptable carrier, and, optionally, other therapeutic ingredients or adjuvants.
  • the instant compositions include those suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered.
  • the pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
  • compositions of this invention can include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt of the compounds of the invention.
  • the compounds of the invention, or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.
  • the pharmaceutical carrier employed can be, for example, a solid, liquid, or gas.
  • solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
  • liquid carriers are sugar syrup, peanut oil, olive oil, and water.
  • gaseous carriers include carbon dioxide and nitrogen.
  • any convenient pharmaceutical media can be employed.
  • water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like can be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like can be used to form oral solid preparations such as powders, capsules and tablets.
  • carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like can be used to form oral solid preparations such as powders, capsules and tablets.
  • tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed.
  • tablets can be coated by standard aqueous or nonaqueous techniques.
  • a tablet containing the composition of this invention can be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants.
  • Compressed tablets can be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
  • compositions of the present invention comprise a compound of the invention (or pharmaceutically acceptable salts thereof) as an active ingredient, a pharmaceutically acceptable carrier, and optionally one or more additional therapeutic agents or adjuvants.
  • the instant compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered.
  • the pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
  • compositions of the present invention suitable for parenteral administration can be prepared as solutions or suspensions of the active compounds in water.
  • a suitable surfactant can be included such as, for example, hydroxypropylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.
  • compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions.
  • the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions.
  • the final injectable form must be sterile and must be effectively fluid for easy syringability.
  • the pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.
  • compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, mouth washes, gargles, and the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations can be prepared, utilizing a compound of the invention, or pharmaceutically acceptable salts thereof, via conventional processing methods. As an example, a cream or ointment is prepared by mixing hydrophilic material and water, together with about 5 wt% to about 10 wt% of the compound, to produce a cream or ointment having a desired consistency.
  • compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories can be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in molds.
  • the pharmaceutical formulations described above can include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like.
  • other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient
  • an effective amount is a therapeutically effective amount. In a still further aspect, an effective amount is a prophylactically effective amount.
  • the pharmaceutical composition is administered to a mammal.
  • the mammal is a human.
  • the human is a patient.
  • the pharmaceutical composition is used to treat a disorder associated with TXNIP activity such as, for example, a disorder associated with elevated TXNIP (e.g., diabetes).
  • a disorder associated with elevated TXNIP e.g., diabetes
  • the pharmaceutical composition is used to treat a disorder of hepatic glucose regulation dysfunction.
  • the disorder associated with elevated TXNIP is diabetes.
  • the diabetes is Type I diabetes, Type II diabetes, or gestational diabetes.
  • the diabetes is Type I diabetes.
  • the diabetes is Type II diabetes.
  • the diabetes is gestational diabetes.
  • compositions can be prepared from the disclosed compounds. It is also understood that the disclosed compositions can be employed in the disclosed methods of using.
  • a disorder associated with TXNIP activity such as, for example, disorders associated with elevated TXNIP and/or elevated glucagon levels (e.g., diabetes).
  • the disclosed compounds exhibit modulation of TXNIP activity.
  • the disclosed compounds exhibit inhibition of TXNIP activity.
  • each disclosed derivative can be optionally further substituted. It is also contemplated that any one or more derivative can be optionally omitted from the invention. It is understood that a disclosed compound can be provided by the disclosed methods. It is also understood that the disclosed compounds can be employed in the disclosed methods of using.
  • compound having a structure represented by a formula: wherein n is 0, 1, or 2; wherein p is 1, 2, 3, or 4; wherein q is 0 or 1; wherein R 1 is -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, -(C1-C4 alkyl)(C1-C4 alkoxy), -(C1-C4 alkyl)CO 2 H, or Cy 1 ; wherein Cy 1 , when present, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalky
  • n is 0, 1, or 2; wherein p is 0, 1, 2, 3, or 4; wherein q is 0 or 1; wherein R 1 is -NH 2 , - OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, -(C1-C4 alkyl)(C1-C4 alkoxy), -(C1-C4 alkyl)CO 2 H, or Cy 1 ; wherein Cy 1 , when present, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1
  • n is 0, 1, or 2; wherein p is 0, 1, 2, 3, or 4; wherein q is 0 or 1; wherein R 1 is -NH 2 , - OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, -(C1-C4 alkyl)(C1-C4 alkoxy), -(C1-C4 alkyl)CO 2 H, or Cy 1 ; wherein Cy 1 , when present, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl,
  • n is 0, 1, or 2; wherein q is 0 or 1; wherein R 1 is -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, or Cy 1 ; wherein Cy 1 , when present, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R 2 is hydrogen or C1-C4 alkyl, or
  • n is 0, 1, or 2, wherein q is 0 or 1; wherein R 1 is -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, -(C1-C4 alkyl)(C1-C4 alkoxy), -(C1-C4 alkyl)CO 2 H, or Cy 1 ; wherein Cy 1 , when present, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C
  • the compound has a structure represented by a formula: or a pharmaceutically acceptable salt thereof.
  • the compound has a structure represented by a formula: or a pharmaceutically acceptable salt thereof.
  • the compound has a structure represented by a formula: or a pharmaceutically acceptable salt thereof.
  • the compound has a structure represented by a formula: or a pharmaceutically acceptable salt thereof.
  • the compound has a structure represented by a formula: or a pharmaceutically acceptable salt thereof.
  • the compound has a structure represented by a formula: or a pharmaceutically acceptable salt thereof.
  • the compound has a structure represented by a formula: or a pharmaceutically acceptable salt thereof.
  • the compound has a structure represented by a formula: or a pharmaceutically acceptable salt thereof.
  • the compound has a structure represented by a formula: or a pharmaceutically acceptable salt thereof.
  • the compound has a structure represented by a formula: or a pharmaceutically acceptable salt thereof.
  • the compound has a structure represented by a formula: or a pharmaceutically acceptable salt thereof.
  • the compound is not:
  • the compound is not:
  • the compound is not:
  • the compound has a structure represented by a formula:
  • the compound has a structure represented by a formula selected from:
  • R 1 is -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, or Cy 1 ; each of R 5a , R 5b , R 5c , and R 5d is independently hydrogen, halogen, -NH 2 , -CN, -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, - CO 2 (C1-C4 alkyl), -CO 2 H, -CO 2 NH 2 , -NHC(O)Cy 3 , -NHC(O)(C1-C4 alkyl), or Cy 3
  • R 1 is -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, or Cy 1 ; each of R 5a , R 5b , R 5c , and R 5d is independently hydrogen, halogen, -NH 2 , -CN, -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, -CO 2 (C1-C4 alkyl), - CO 2 H, -CO 2 NH 2 , -NHC(O)Cy 3 , -NHC(O)(C1-C4 alkyl), or Cy 3 ; and R 8a is hydrogen and R
  • R 1 is methyl and each of R 3 and R 4 is hydrogen then each of R 5a , R 5b , R 5c , and R 5d is independently hydrogen, fluorine, -NH 2 , -OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, or Cy 3 .
  • R 1 is methyl, each of R 3 and R 4 is hydrogen, and each of R 5a , R 5b , R 5c , and R 5d is independently hydrogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, or Cy 3 .
  • R 1 is methyl, each of R 3 and R 4 is hydrogen, and R 5b is fluorine.
  • n is 0, 1, or 2. In a further aspect, n is 0 or 1. In a still further aspect, n is 1 or 2. In yet a further aspect, n is 0. In an even further aspect, n is 1. In a still further aspect, n is 2.
  • q is 0 or 1. In a still further aspect, q is 0. In yet a further aspect, q is 1.
  • p is 0, 1, 2, 3, or 4. In a further aspect, p is 1, 2, 3, or 4. In a further aspect, p is 0 or 1. In a still further aspect, p is 0. In yet a further aspect, p is 1.
  • each of p and q is independently 0 or 1. In a still further aspect, p is 0 and q is 1. In yet a further aspect, p is 1 and q is 0. In an even further aspect, p is 0 or 1 and q is 0. In a still further aspect, q is 0 or 1 and p is 0. In yet a further aspect, p is 0 or 1 and q is 1. In an even further aspect, q is 0 or 1 and p is 1. In a still further aspect, each of p and q is 0. In yet a further aspect, each of p and q is 1.
  • A is O, NR 6a , or CHR 6b . In a further aspect, A is O or NR 6a . In a still further aspect, A is O or CHR 6b . In yet a further aspect, A is NR 6a or CHR 6b . In an even further aspect, A is O. In a still further aspect, A is NR 6a . In yet a further aspect, A is CHR 6b . In an even further aspect, A is NH. In a still further aspect, A is CH 2 .
  • R 1 is -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, -(C1-C4 alkyl)(C1-C4 alkoxy), -(C1-C4 alkyl)CO 2 H, or Cy 1 .
  • each of R 1 and R 3 are covalently bonded together and, together with the intermediate atoms, comprise a 5- to 7-membered heterocycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • each of R 1 and R 3 are covalently bonded together and, together with the intermediate atoms, comprise a 5- to 7-membered heterocycloalkyl substituted with 0, 1, or 2 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • each of R 1 and R 3 are covalently bonded together and, together with the intermediate atoms, comprise a 5- to 7-membered heterocycloalkyl substituted with 0 or 1 group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • each of R 1 and R 3 are covalently bonded together and, together with the intermediate atoms, comprise a 5- to 7-membered heterocycloalkyl monosubstituted with a group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • each of R 1 and R 3 are covalently bonded together and, together with the intermediate atoms, comprise an unsubstituted 5- to 7-membered heterocycloalkyl.
  • R 1 is -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, or Cy 1 .
  • R 1 is -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, or Cy 1 .
  • R 1 is -NH 2 , -OH, methyl, ethyl, n-propyl, i-propyl, -CH 2 F, -CH 2 Cl, -CH 2 CH 2 F, -CH 2 CH 2 Cl, -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CH 2 Cl, -CH(CH 3 )CH 2 F, - CH(CH 3 )CH 2 Cl, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH(CH 3 )CH 3 , -CH 2 OH, - CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -CH(CH 3 )CH 2 OH, -NHCH 3 , -NHCH 2 CH 3 , - NHCH 2 CH 2 CH 3 , -NHCH(CH 3 )CH 3 , -N(CH 3 ) 2 , -N(CH 2 CH 3 )
  • R 1 is - NH 2 , -OH, methyl, ethyl, -CH 2 F, -CH 2 Cl, -CH 2 CH 2 F, -CH 2 CH 2 Cl, -OCH 3 , -OCH 2 CH 3 , - CH 2 OH, -CH 2 CH 2 OH, -NHCH 3 , -NHCH 2 CH 3 , -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , - N(CH 3 )(CH 2 CH 3 ), -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 ,-CH 2 CO 2 H, -CH 2 CH 2 CO 2 H, or Cy 1 .
  • R 1 is -NH 2 , -OH, methyl, -CH 2 F, -CH 2 Cl, -OCH 3 , -CH 2 OH, -NHCH 3 , - N(CH 3 ) 2 , -CH 2 OCH 3 ,-CH 2 CO 2 H, or Cy 1 .
  • R 1 is -NH 2 , -OH, methyl, ethyl, n-propyl, i-propyl, -CH 2 F, -CH 2 Cl, -CH 2 CH 2 F, -CH 2 CH 2 Cl, -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CH 2 Cl, -CH(CH 3 )CH 2 F, - CH(CH 3 )CH 2 Cl, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH(CH 3 )CH 3 , -NHCH 3 , - NHCH 2 CH 3 , -NHCH 2 CH 2 CH 3 , -NHCH(CH 3 )CH 3 , -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , - N(CH 2 CH 2 CH 3 ) 2 , -N(CH(CH 3 )CH 3 ) 2 , -N(CH(CH 3
  • R 1 is -NH 2 , -OH, methyl, ethyl, -CH 2 F, -CH 2 Cl, -CH 2 CH 2 F, -CH 2 CH 2 Cl, -OCH 3 , - OCH 2 CH 3 , -NHCH 3 , -NHCH 2 CH 3 , -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , -N(CH 3 )(CH 2 CH 3 ), or Cy 1 .
  • R 1 is -NH 2 , -OH, methyl, -CH 2 F, -CH 2 Cl, -OCH 3 , -NHCH 3 , - N(CH 3 ) 2 , or Cy 1 .
  • R 1 is -OH, methyl, ethyl, n-propyl, i-propyl, -CH 2 F, - CH 2 Cl, -CH 2 CH 2 F, -CH 2 CH 2 Cl, -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CH 2 Cl, -CH(CH 3 )CH 2 F, - CH(CH 3 )CH 2 Cl, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH(CH 3 )CH 3 , -NHCH 3 , - NHCH 2 CH 3 , -NHCH 2 CH 2 CH 3 , -NHCH(CH 3 )CH 3 , -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , - N(CH 2 CH 2 CH 3 ) 2 , -N(CH(CH 3 )CH 3 ) 2 , -N(CH 3 )(CH 3 )(CH
  • R 1 is -OH, methyl, ethyl, -CH 2 F, -CH 2 Cl, -CH 2 CH 2 F, -CH 2 CH 2 Cl, -OCH 3 , -OCH 2 CH 3 , - NHCH 3 , -NHCH 2 CH 3 , -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , -N(CH 3 )(CH 2 CH 3 ), or Cy 1 .
  • R 1 is -OH, methyl, -CH 2 F, -CH 2 Cl, -OCH 3 , -NHCH 3 , -N(CH 3 ) 2 , or Cy 1 .
  • R 1 is C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, or (C1-C4)(C1-C4) dialkylamino, or Cy 1 .
  • R 1 is methyl, ethyl, n-propyl, i-propyl, -CH 2 F, -CH 2 Cl, -CH 2 CH 2 F, -CH 2 CH 2 Cl, -CH 2 CH 2 CH 2 F, - CH 2 CH 2 CH 2 Cl, -CH(CH 3 )CH 2 F, -CH(CH 3 )CH 2 Cl, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , - OCH(CH 3 )CH 3 , -NHCH 3 , -NHCH 2 CH 3 , -NHCH 2 CH 2 CH 3 , -NHCH(CH 3 )CH 3 , -N(CH 3 ) 2 , - N(CH 2 CH 3 ) 2 , -N(CH 2 CH 2 CH 3 ) 2 , -N(CH(CH 3 )CH 3 ) 2 , -N(CH 3 )(CH 2 CH 3 )(CH 2 CH 3
  • R 1 is methyl, ethyl, -CH 2 F, -CH 2 Cl, -CH 2 CH 2 F, -CH 2 CH 2 Cl, -OCH 3 , - OCH 2 CH 3 , -NHCH 3 , -NHCH 2 CH 3 , -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , -N(CH 3 )(CH 2 CH 3 ), or Cy 1 .
  • R 1 is methyl, -CH 2 F, -CH 2 Cl, -OCH 3 , -NHCH 3 , -N(CH 3 ) 2 , or Cy 1 .
  • R 1 is -NH 2 , -OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, or Cy 1 .
  • R 1 is -NH 2 , - OH, methyl, ethyl, n -propyl, i -propyl, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , - OCH(CH 3 )CH 3 , -NHCH 3 , -NHCH 2 CH 3 , -NHCH 2 CH 2 CH 3 , -NHCH(CH 3 )CH 3 , -N(CH 3 ) 2 , - N(CH 2 CH 3 ) 2 , -N(CH 2 CH 2 CH 3 ) 2 , -N(CH(CH 3 )CH 3 ) 2 , -N(CH 3 )(CH 2 CH 3 ), or Cy 1 .
  • R 1 is -NH 2 , -OH, methyl, ethyl, -OCH 3 , -OCH 2 CH 3 , -NHCH 3 , -NHCH 2 CH 3 , -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , -N(CH 3 )(CH 2 CH 3 ), or Cy 1 .
  • R 1 is -NH 2 , - OH, methyl, -OCH 3 , -NHCH 3 , -N(CH 3 ) 2 , or Cy 1 .
  • R 1 is -OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, or Cy 1 .
  • R 1 is -OH, methyl, ethyl, n-propyl, i-propyl, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH(CH 3 )CH 3 , -NHCH 3 , - NHCH 2 CH 3 , -NHCH 2 CH 2 CH 3 , -NHCH(CH 3 )CH 3 , -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , - N(CH 2 CH 2 CH 3 ) 2 , -N(CH(CH 3 )CH 3 ) 2 , -N(CH 3 )(CH 2 CH 3 ), or Cy 1 .
  • R 1 is -OH, methyl, ethyl, -OCH 3 , -OCH 2 CH 3 , -NHCH 3 , -NHCH 2 CH 3 , -N(CH 3 ) 2 , - N(CH 2 CH 3 ) 2 , -N(CH 3 )(CH 2 CH 3 ), or Cy 1 .
  • R 1 is -OH, methyl, -OCH 3 , -NHCH 3 , -N(CH 3 ) 2 , or Cy 1 .
  • R 1 is -NH 2 , -OH, C1-C4 alkyl, C1-C4 alkoxy, or Cy 1 .
  • R 1 is -NH 2 , -OH, methyl, ethyl, n -propyl, i -propyl, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH(CH 3 )CH 3 , or Cy 1 .
  • R 1 is -NH 2 , -OH, methyl, ethyl, -OCH 3 , -OCH 2 CH 3 , or Cy 1 .
  • R 1 is -NH 2 , -OH, methyl, -OCH 3 , or Cy 1 .
  • R 1 is -OH, C1-C4 alkyl, C1-C4 alkoxy, or Cy 1 . .
  • R 1 is -OH, methyl, ethyl, n -propyl, i -propyl, -OCH 3 , -OCH 2 CH 3 , - OCH 2 CH 2 CH 3 , -OCH(CH 3 )CH 3 , or Cy 1 .
  • R 1 is -OH, methyl, ethyl, - OCH 3 , -OCH 2 CH 3 , or Cy 1 .
  • R 1 is -OH, methyl, -OCH 3 , or Cy 1 .
  • R 1 is C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 alkoxy.
  • R 1 is methyl, ethyl, n -propyl, i -propyl, -CH 2 F, -CH 2 Cl, -CH 2 CH 2 F, - CH 2 CH 2 Cl, -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CH 2 Cl, -CH(CH 3 )CH 2 F, -CH(CH 3 )CH 2 Cl, -OCH 3 , - OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , or -OCH(CH 3 )CH 3 .
  • R 1 is methyl, ethyl, -CH 2 F, -CH 2 Cl, -CH 2 CH 2 F, -CH 2 CH 2 Cl, -OCH 3 , or -OCH 2 CH 3 . In yet a further aspect, R 1 is methyl, -CH 2 F, -CH 2 Cl, or -OCH 3 .
  • R 1 is Cy 1 .
  • R 1 is C1-C4 haloalkyl.
  • R 1 is-CH 2 F, -CH 2 Cl, -CH 2 CH 2 F, -CH 2 CH 2 Cl, -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CH 2 Cl, -CH(CH 3 )CH 2 F, or -CH(CH 3 )CH 2 Cl.
  • R 1 is -CH 2 F, -CH 2 Cl, -CH 2 CH 2 F, or - CH 2 CH 2 Cl.
  • R 1 is -CH 2 F or -CH 2 Cl.
  • R 1 is C1-C4 alkyl. In a still further aspect, R 1 is methyl, ethyl, n -propyl, i -propyl, n -butyl, i -butyl, s -butyl, or t -butyl. In yet a further aspect, R 1 is methyl, ethyl, n -propyl, or i -propyl. In an even further aspect, R 1 is methyl or ethyl. In a still further aspect, R 1 is ethyl. In yet a further aspect, R 1 is methyl.
  • each of R 1 and R 3 are covalently bonded together and, together with the intermediate atoms, comprise a 5- to 6-membered heterocycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • R 1 and R 3 are covalently bonded together and, together with the intermediate atoms, comprise a 5- to 6-membered heterocycloalkyl substituted with 0, 1, or 2 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • R 1 and R 3 are covalently bonded together and, together with the intermediate atoms, comprise a 5- to 6-membered heterocycloalkyl substituted with 0 or 1 group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • R 1 and R 3 are covalently bonded together and, together with the intermediate atoms, comprise a 5- to 6-membered heterocycloalkyl monosubstituted with a group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • R 1 and R 3 are covalently bonded together and, together with the intermediate atoms, comprise an unsubstituted 5- to 6-membered heterocycloalkyl.
  • each of R 1 and R 3 are covalently bonded together and, together with the intermediate atoms, comprise a 5-membered heterocycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • each of R 1 and R 3 are covalently bonded together and, together with the intermediate atoms, comprise a 6-membered heterocycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • each of R 1 and R 3 are covalently bonded together and, together with the intermediate atoms, comprise a 7-membered heterocycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • R 2 is hydrogen or C1-C4 alkyl, or wherein each of R 1 and R 2 are covalently bonded together and, together with the intermediate atoms, comprise a 3- to 6-membered heterocycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino.
  • R 2 is hydrogen or C1-C4 alkyl. In a still further aspect, R 2 is hydrogen.
  • R 2 is hydrogen, methyl, ethyl, isopropyl, n-propyl, isobutyl, n-butyl, s-butyl, or t-butyl. In a still further aspect, R 2 is hydrogen, methyl, ethyl, isopropyl, or n-propyl. In yet a further aspect, R 2 is hydrogen, methyl, or ethyl. In an even further aspect, R 2 is hydrogen or methyl. In a still further aspect, R 2 is hydrogen or ethyl.
  • R 2 is methyl, ethyl, isopropyl, n-propyl, isobutyl, n-butyl, s-butyl, or t-butyl. In a still further aspect, R 2 is methyl, ethyl, isopropyl, or n-propyl. In yet a further aspect, R 2 is methyl, or ethyl. In an even further aspect, R 2 is methyl. In a still further aspect, R 2 is ethyl.
  • each of R 1 and R 2 are covalently bonded together and, together with the intermediate atoms, comprise a 3- to 6-membered heterocycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino.
  • each of R 1 and R 2 are covalently bonded together and, together with the intermediate atoms, comprise a 3- to 6-membered heterocycloalkyl substituted with 0, 1, or 2 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino.
  • each of R 1 and R 2 are covalently bonded together and, together with the intermediate atoms, comprise a 3- to 6-membered heterocycloalkyl substituted with 0 or 1 group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino.
  • each of R 1 and R 2 are covalently bonded together and, together with the intermediate atoms, comprise a 3- to 6-membered heterocycloalkyl monosubstituted with a group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino.
  • each of R 1 and R 2 are covalently bonded together and, together with the intermediate atoms, comprise an unsubstituted 3- to 6-membered heterocycloalkyl.
  • each of R 1 and R 2 are covalently bonded together and, together with the intermediate atoms, comprise a 3- to 5-membered heterocycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino.
  • each of R 1 and R 2 are covalently bonded together and, together with the intermediate atoms, comprise a 3- to 4-membered heterocycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino.
  • each of R 1 and R 2 are covalently bonded together and, together with the intermediate atoms, comprise a 6-membered heterocycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino.
  • each of R 1 and R 2 are covalently bonded together and, together with the intermediate atoms, comprise a 5-membered heterocycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino.
  • each of R 1 and R 2 are covalently bonded together and, together with the intermediate atoms, comprise a 4-membered heterocycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino.
  • each of R 1 and R 2 are covalently bonded together and, together with the intermediate atoms, comprise a 3-membered heterocycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino.
  • R 3 is hydrogen or C1-C4 alkyl. In a further aspect, R 3 is hydrogen.
  • R 3 is hydrogen, methyl, ethyl, isopropyl, n-propyl, isobutyl, n-butyl, s-butyl, or t-butyl. In a still further aspect, R 3 is hydrogen, methyl, ethyl, isopropyl, or n-propyl. In yet a further aspect, R 3 is hydrogen, methyl, or ethyl. In an even further aspect, R 3 is hydrogen or methyl. In a still further aspect, R 3 is hydrogen or ethyl.
  • R 3 is methyl, ethyl, isopropyl, n-propyl, isobutyl, n-butyl, s-butyl, or t-butyl. In a still further aspect, R 3 is methyl, ethyl, isopropyl, or n-propyl. In yet a further aspect, R 3 is methyl, or ethyl. In an even further aspect, R 3 is methyl. In a still further aspect, R 3 is ethyl.
  • R 4 is hydrogen, halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, or Cy 2 . In a further aspect, R 4 is hydrogen.
  • R 4 is -F, -Cl, -NH 2 , -OH, methyl, ethyl, n-propyl, i- propyl, -CH 2 F, -CH 2 Cl, -CH 2 CH 2 F, -CH 2 CH 2 Cl, -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CH 2 Cl, - CH(CH 3 )CH 2 F, -CH(CH 3 )CH 2 Cl, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH(CH 3 )CH 3 , - NHCH 3 , -NHCH 2 CH 3 , -NHCH 2 CH 2 CH 3 , -NHCH(CH 3 )CH 3 , -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , - N(CH 2 CH 2 CH 3 ) 2 , -N(CH(CH 3 )CH 3 , -N
  • R 4 is -F, -Cl, -NH 2 , -OH, methyl, ethyl, -CH 2 F, -CH 2 Cl, -CH 2 CH 2 F, -CH 2 CH 2 Cl, -OCH 3 , -OCH 2 CH 3 , -NHCH 3 , -NHCH 2 CH 3 , -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , -N(CH 3 )(CH 2 CH 3 ), or Cy 2 .
  • R 4 is -F, -Cl, -NH 2 , -OH, methyl, -CH 2 F, -CH 2 Cl, -OCH 3 , - NHCH 3 , -N(CH 3 ) 2 , or Cy 2 .
  • R 4 is C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, or (C1-C4)(C1-C4) dialkylamino, or Cy 2 .
  • R 4 is methyl, ethyl, n-propyl, i-propyl, -CH 2 F, -CH 2 Cl, -CH 2 CH 2 F, -CH 2 CH 2 Cl, -CH 2 CH 2 CH 2 F, - CH 2 CH 2 CH 2 Cl, -CH(CH 3 )CH 2 F, -CH(CH 3 )CH 2 Cl, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , - OCH(CH 3 )CH 3 , -NHCH 3 , -NHCH 2 CH 3 , -NHCH 2 CH 2 CH 3 , -NHCH(CH 3 )CH 3 , -N(CH 3 ) 2 , - N(CH 2 CH 3 ) 2 , -N(CH 2 CH 2 CH 3 ) 2 , -N(CH(CH 3 )CH 3 ) 2 , -N(CH 3 )(CH 2 CH 3 )(CH 2 CH 3
  • R 4 is methyl, ethyl, -CH 2 F, -CH 2 Cl, -CH 2 CH 2 F, -CH 2 CH 2 Cl, -OCH 3 , - OCH 2 CH 3 , -NHCH 3 , -NHCH 2 CH 3 , -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , -N(CH 3 )(CH 2 CH 3 ), or Cy 2 .
  • R 4 is methyl, -CH 2 F, -CH 2 Cl, -OCH 3 , -NHCH 3 , -N(CH 3 ) 2 , or Cy 2 .
  • R 4 is -F, -Cl, -NH 2 , -OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, or Cy 2 .
  • R 4 is -F, -Cl, -NH 2 , -OH, methyl, ethyl, n-propyl, i-propyl, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , - OCH(CH 3 )CH 3 , NHCH 3 , NHCH 2 CH 3 , NHCH 2 CH 2 CH 3 , NHCH(CH 3 )CH 3 , N(CH 3 ) 2 , - N(CH 2 CH 3 ) 2 , -N(CH 2 CH 2 CH 3 ) 2 , -N(CH(CH 3 )CH 3 ) 2 , -N(CH 3 )(CH 2 CH 3 ), or Cy 2 .
  • R 4 is -F, -Cl, -NH 2 , -OH, methyl, ethyl, -OCH 3 , -OCH 2 CH 3 , -NHCH 3 , - NHCH 2 CH 3 , -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , -N(CH 3 )(CH 2 CH 3 ), or Cy 2 .
  • R 4 is -F, -Cl, -NH 2 , -OH, methyl, -OCH 3 , -NHCH 3 , -N(CH 3 ) 2 , or Cy 2 .
  • R 4 is -F, -Cl, -NH 2 , -OH, C1-C4 alkyl, C1-C4 alkoxy, or Cy 2 .
  • R 4 is -F, -Cl, -NH 2 , -OH, methyl, ethyl, n-propyl, i-propyl, - OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH(CH 3 )CH 3 , or Cy 2 .
  • R 4 is -F, -Cl, -NH 2 , -OH, methyl, ethyl, -OCH 3 , -OCH 2 CH 3 , or Cy 2 .
  • R 4 is -F, -Cl, -NH 2 , -OH, methyl, -OCH 3 , or Cy 2 .
  • R 4 is C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 alkoxy.
  • R 4 is methyl, ethyl, n -propyl, i -propyl, -CH 2 F, -CH 2 Cl, -CH 2 CH 2 F, - CH 2 CH 2 Cl -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CH 2 Cl, -CH(CH 3 )CH 2 F, -CH(CH 3 )CH 2 Cl, -OCH 3 , - OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , or -OCH(CH 3 )CH 3 .
  • R 4 is methyl, ethyl, -CH 2 F, -CH 2 Cl, -CH 2 CH 2 F, -CH 2 CH 2 Cl, -OCH 3 , or -OCH 2 CH 3 . In yet a further aspect, R 4 is methyl, -CH 2 F, -CH 2 Cl, or -OCH 3 .
  • R 4 is Cy 2 .
  • R 4 is C1-C4 haloalkyl.
  • R 4 is - CH 2 F, -CH 2 Cl, -CH 2 CH 2 F, -CH 2 CH 2 Cl, -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CH 2 Cl, -CH(CH 3 )CH 2 F, or -CH(CH 3 )CH 2 Cl.
  • R 4 is -CH 2 F, -CH 2 Cl, -CH 2 CH 2 F, or - CH 2 CH 2 Cl.
  • R 4 is -CH 2 F or -CH 2 Cl.
  • R 4 is C1-C4 alkyl. In a still further aspect, R 4 is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl. In yet a further aspect, R 4 is methyl, ethyl, n-propyl, or i-propyl. In an even further aspect, R 4 is methyl or ethyl. In a still further aspect, R 4 is ethyl. In yet a further aspect, R 4 is methyl.
  • each of R 5a , R 5b , R 5c , and R 5d is independently hydrogen, halogen, -NH 2 , -CN, -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, -CO 2 (C1-C4 alkyl), -CO 2 H, -CO 2 NH 2 , - NHC(O)Cy 3 , -NHC(O)(C1-C4 alkyl), or Cy 3 .
  • each of R 5a , R 5b , R 5c , and R 5d is independently hydrogen, halogen, -NH 2 , -CN, -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, -CO 2 (C1-C4 alkyl), -CO 2 H, -CO 2 NH 2 , - NHC(O)Cy 3 , -NHC(O)(C1-C4 alkyl), or Cy 3 .
  • R 5a , R 5b , R 5c , and R 5d is not hydrogen.
  • one of R 5a , R 5b , R 5c , and R 5d is hydrogen.
  • two of R 5a , R 5b , R 5c , and R 5d is hydrogen.
  • three of R 5a , R 5b , R 5c , and R 5d are hydrogen.
  • each of R 5a , R 5b , and R 5d is independently hydrogen, halogen, - NH 2 , -CN, -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, -CO 2 (C1-C4 alkyl), -CO 2 H, -CO 2 NH 2 , -NHC(O)Cy 3 , - NHC(O)(C1-C4 alkyl), or Cy 3 ; and R 5c is hydrogen, halogen, -CN, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, - CO 2 (C
  • each of R 5a , R 5b , R 5c , and R 5d is independently hydrogen, - F, -Cl, -NH 2 , -CN, -OH, methyl, ethyl, n -propyl, i -propyl, -CH 2 F, -CH 2 Cl, -CH 2 CH 2 F, - CH 2 CH 2 Cl, -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CH 2 Cl, -CH(CH 3 )CH 2 F, -CH(CH 3 )CH 2 Cl, -OCH 3 , - OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH(CH 3 )CH 3 , -OCF 3 , -OCH 2 CF 3 , -OCH 2 CH 2 CF 3 , - OCH(CH 3 )CF 3 , -NHCH 3 , -NHCH 2 CH 3 , -NHCH 2 CH 3 , -
  • each of R 5a , R 5b , R 5c , and R 5d is independently hydrogen, -F, -Cl, -NH 2 , - CN, -OH, methyl, ethyl, -CH 2 F, -CH 2 Cl, -CH 2 CH 2 F, -CH 2 CH 2 Cl, -OCH 3 , -OCH 2 CH 3 , - OCF 3 , -OCH 2 CF 3 , -NHCH 3 , -NHCH 2 CH 3 , -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , -N(CH 3 )(CH 2 CH 3 ), - CO 2 CH 3 , -CO 2 CH 2 CH 3 , -CO 2 H, -CO 2 NH 2 , -NHC(O)Cy 3 , -NHC(O)CH 3 , - NHC(O)CH 2 CH 3 , or Cy 3 .
  • each of R 5a , R 5b , R 5c , and R 5d is independently hydrogen, -F, -Cl, -NH 2 , -CN, -OH, methyl, -CH 2 F, -CH 2 Cl, -OCH 3 , - OCF 3 , -NHCH 3 , -N(CH 3 ) 2 , -CO 2 CH 3 , -CO 2 H, -CO 2 NH 2 , -NHC(O)Cy 3 , -NHC(O)CH 3 , or Cy3.
  • each of R 5a , R 5b , R 5c , and R 5d is independently hydrogen, - F, -Cl, -NH 2 , -CN, -OH, methyl, ethyl, n-propyl, i-propyl, -CH 2 F, -CH 2 Cl, -CH 2 CH 2 F, - CH 2 CH 2 Cl, -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CH 2 Cl, -CH(CH 3 )CH 2 F, -CH(CH 3 )CH 2 Cl, -OCH 3 , - OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH(CH 3 )CH 3 , -NHCH 3 , -NHCH 2 CH 3 , -NHCH 2 CH 2 CH 3 , - NHCH(CH 3 )CH 3 , -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 ,
  • each of R 5a , R 5b , R 5c , and R 5d is independently hydrogen, -F, -Cl, -NH 2 , -CN, -OH, methyl, ethyl, -CH 2 F, -CH 2 Cl, - CH 2 CH 2 F, -CH 2 CH 2 Cl, -OCH 3 , -OCH 2 CH 3 , -NHCH 3 , -NHCH 2 CH 3 , -N(CH 3 ) 2 , - N(CH 2 CH 3 ) 2 , -N(CH 3 )(CH 2 CH 3 ), -CO 2 CH 3 , -CO 2 CH 2 CH 3 , -CO 2 H, -CO 2 NH 2 , - NHC(O)Cy 3 , -NHC(O)CH 3 , -NHC(O)CH 2 CH 3 , or Cy 3 .
  • each of R 5a , R 5b , R 5c , and R 5d is independently hydrogen, -F, -Cl, -NH 2 , -CN, -OH, methyl, -CH 2 F, - CH 2 Cl, -OCH 3 , -NHCH 3 , -N(CH 3 ) 2 , -CO 2 CH 3 , -CO 2 H, -CO 2 NH 2 , -NHC(O)Cy 3 , - NHC(O)CH 3 , or Cy 3 .
  • each of R 5a , R 5b , R 5c , and R 5d is independently hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, or (C1-C4)(C1-C4) dialkylamino, -CO 2 (C1-C4 alkyl), -CO 2 H, -CO 2 NH 2 , -NHC(O)Cy 3 , -NHC(O)(C1-C4 alkyl), or Cy 3 .
  • each of R 5a , R 5b , R 5c , and R 5d is independently hydrogen, methyl, ethyl, n -propyl, i -propyl, -CH 2 F, -CH 2 Cl, -CH 2 CH 2 F, -CH 2 CH 2 Cl, - CH 2 CH 2 CH 2 F, -CH 2 CH 2 CH 2 Cl, -CH(CH 3 )CH 2 F, -CH(CH 3 )CH 2 Cl, -OCH 3 , -OCH 2 CH 3 , - OCH 2 CH 2 CH 3 , -OCH(CH 3 )CH 3 , -NHCH 3 , -NHCH 2 CH 3 , -NHCH 2 CH 2 CH 3 , - NHCH(CH 3 )CH 3 , -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , -N(CH 2 CH 2 CH 3 ) 2 , -N(CH 2 CH 2 CH 3 )
  • each of R 5a , R 5b , R 5c , and R 5d is independently hydrogen, methyl, ethyl, -CH 2 F, -CH 2 Cl, -CH 2 CH 2 F, -CH 2 CH 2 Cl, -OCH 3 , - OCH 2 CH 3 , -NHCH 3 , -NHCH 2 CH 3 , -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , -N(CH 3 )(CH 2 CH 3 ), - CO 2 CH 3 , -CO 2 CH 2 CH 3 , -CO 2 H, -CO 2 NH 2 , -NHC(O)Cy 3 , -NHC(O)CH 3 , - NHC(O)CH 2 CH 3 , or Cy 3 .
  • each of R 5a , R 5b , R 5c , and R 5d is independently hydrogen, methyl, -CH 2 F, -CH 2 Cl, -OCH 3 , -NHCH 3 , -N(CH 3 ) 2 , -CO 2 CH 3 , - CO 2 H, -CO 2 NH 2 , -NHC(O)Cy 3 , -NHC(O)CH 3 , or Cy 3 .
  • each of R 5a , R 5b , R 5c , and R 5d is independently hydrogen, - F, -Cl, -NH 2 , -CN, -OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, -CO 2 (C1-C4 alkyl), -CO 2 H, -CO 2 NH 2 , -NHC(O)Cy 3 , -NHC(O)(C1-C4 alkyl), or Cy 3 .
  • each of R 5a , R 5b , R 5c , and R 5d is independently hydrogen, -F, -Cl, -NH 2 , -CN, -OH, methyl, ethyl, n -propyl, i -propyl, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH(CH 3 )CH 3 , -NHCH 3 , -NHCH 2 CH 3 , -NHCH 2 CH 2 CH 3 , - NHCH(CH 3 )CH 3 , -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , -N(CH 2 CH 2 CH 3 ) 2 , -N(CH(CH 3 )CH 3 ) 2 , - N(CH 3 )(CH 2 CH 3 ), -CO 2 CH 3 , -CO 2 CH 2 CH 3 , -CO 2 CH 3 , -CO
  • each of R 5a , R 5b , R 5c , and R 5d is independently hydrogen, -F, -Cl, -NH 2 , -CN, -OH, methyl, ethyl, -OCH 3 , -OCH 2 CH 3 , - NHCH 3 , -NHCH 2 CH 3 , -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , -N(CH 3 )(CH 2 CH 3 ), -CO 2 CH 3 , - CO 2 CH 2 CH 3 , -CO 2 H, -CO 2 NH 2 , -NHC(O)Cy 3 , -NHC(O)CH 3 , -NHC(O)CH 2 CH 3 , or Cy 3 .
  • each of R 5a , R 5b , R 5c , and R 5d is independently hydrogen, -F, -Cl, - NH 2 , -CN, -OH, methyl, -OCH 3 , -NHCH 3 , -N(CH 3 ) 2 , -CO 2 CH 3 , -CO 2 H, -CO 2 NH 2 , - NHC(O)Cy 3 , -NHC(O)CH 3 , or Cy 3 .
  • each of R 5a , R 5b , R 5c , and R 5d is independently hydrogen, - F, -Cl, -NH 2 , -CN, -OH, C1-C4 alkyl, C1-C4 alkoxy, -CO 2 (C1-C4 alkyl), -CO 2 H, - CO 2 NH 2 , -NHC(O)Cy 3 , -NHC(O)(C1-C4 alkyl), or Cy 3 .
  • each of R 5a , R 5b , R 5c , and R 5d is independently hydrogen, -F, -Cl, -NH 2 , -CN, -OH, methyl, ethyl, n- propyl, i -propyl, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH(CH 3 )CH 3 , -CO 2 CH 3 , - CO 2 CH 2 CH 3 , -CO 2 CH 2 CH 2 CH 3 , -CO 2 CH(CH 3 ) 2 , -CO 2 H, -CO 2 NH 2 , -NHC(O)Cy 3 , - NHC(O)CH 3 , -NHC(O)CH 2 CH 3 , -NHC(O)CH 2 CH 2 CH 3 , -NHC(O)CH(CH 3 ) 2 , or Cy 3 .
  • each of R 5a , R 5b , R 5c , and R 5d is independently hydrogen, -F, -Cl, -NH 2 , - CN, -OH, methyl, ethyl, -OCH 3 , -OCH 2 CH 3 , -CO 2 CH 3 , -CO 2 CH 2 CH 3 , -CO 2 H, -CO 2 NH 2 , -NHC(O)Cy 3 , -NHC(O)CH 3 , -NHC(O)CH 2 CH 3 , or Cy 3 .
  • each of R 5a , R 5b , R 5c , and R 5d is independently hydrogen, -F, -Cl, -NH 2 , -CN, -OH, methyl, -OCH 3 , - CO 2 CH 3 , -CO 2 H, -CO 2 NH 2 , -NHC(O)Cy 3 , -NHC(O)CH 3 , or Cy 3 .
  • each of R 5a , R 5b , R 5c , and R 5d is independently hydrogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, or Cy 3 .
  • each of R 5a , R 5b , R 5c , and R 5d is independently hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 alkoxy.
  • each of R 5a , R 5b , R 5c , and R 5d is independently hydrogen, methyl, ethyl, n-propyl, i-propyl, -CH 2 F, -CH 2 Cl, - CH 2 CH 2 F, -CH 2 CH 2 Cl, -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CH 2 Cl, -CH(CH 3 )CH 2 F, - CH(CH 3 )CH 2 Cl, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , or -OCH(CH 3 )CH 3 .
  • each of R 5a , R 5b , R 5c , and R 5d is independently hydrogen, methyl, ethyl, -CH 2 F, - CH 2 Cl, -CH 2 CH 2 F, -CH 2 CH 2 Cl, -OCH 3 , or -OCH 2 CH 3 .
  • each of R 5a , R 5b , R 5c , and R 5d is independently hydrogen, methyl, -CH 2 F, -CH 2 Cl, or -OCH 3 .
  • each of R 5a , R 5b , R 5c , and R 5d is independently hydrogen or Cy3.
  • each of R 5a , R 5b , R 5c , and R 5d is independently hydrogen, - CO 2 (C1-C4 alkyl), -CO 2 H, -CO 2 NH 2 , -NHC(O)Cy 3 , or -NHC(O)(C 1-C4 alkyl).
  • each of R 5a , R 5b , R 5c , and R 5d is independently hydrogen, -CO 2 CH 3 , - CO 2 CH 2 CH 3 , -CO 2 CH 2 CH 2 CH 3 , -CO 2 CH(CH 3 ) 2 , -CO 2 H, -CO 2 NH 2 , -NHC(O)Cy 3 , - NHC(O)CH 3 , -NHC(O)CH 2 CH 3 , -NHC(O)CH 2 CH 2 CH 3 , or -NHC(O)CH(CH 3 ) 2 .
  • each of R 5a , R 5b , R 5c , and R 5d is independently hydrogen, -CO 2 CH 3 , - CO 2 CH 2 CH 3 , -CO 2 H, -CO 2 NH 2 , -NHC(O)Cy 3 , -NHC(O)CH 3 , or -NHC(O)CH 2 CH 3 .
  • each of R 5a , R 5b , R 5c , and R 5d is independently hydrogen, -CO 2 CH 3 , - CO 2 H, -CO 2 NH 2 , -NHC(O)Cy 3 , or -NHC(O)CH 3 .
  • each of R 5a , R 5b , R 5c , and R 5d is independently hydrogen or C1-C4 haloalkyl.
  • each of R 5a , R 5b , R 5c , and R 5d is independently hydrogen, -CH 2 F, -CH 2 Cl, -CH 2 CH 2 F, -CH 2 CH 2 Cl, -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CH 2 Cl, - CH(CH 3 )CH 2 F, or -CH(CH 3 )CH 2 Cl.
  • each of R 5a , R 5b , R 5c , and R 5d is independently hydrogen, -CH 2 F, -CH 2 Cl, -CH 2 CH 2 F, or -CH 2 CH 2 Cl. In yet a further aspect, each of R 5a , R 5b , R 5c , and R 5d is independently hydrogen, -CH 2 F or -CH 2 Cl.
  • each of R 5a , R 5b , R 5c , and R 5d is independently hydrogen or C1-C4 alkyl. In a still further aspect, each of R 5a , R 5b , R 5c , and R 5d is independently hydrogen, methyl, ethyl, n -propyl, i -propyl, n -butyl, i -butyl, s -butyl, or t -butyl. In yet a further aspect, each of R 5a , R 5b , R 5c , and R 5d is independently hydrogen, methyl, ethyl, n- propyl, or i -propyl.
  • each of R 5a , R 5b , R 5c , and R 5d is independently hydrogen, methyl or ethyl. In a still further aspect, each of R 5a , R 5b , R 5c , and R 5d is independently hydrogen or ethyl. In yet a further aspect, each of R 5a , R 5b , R 5c , and R 5d is independently hydrogen or methyl.
  • each of R 5a , R 5b , R 5c , and R 5d is independently hydrogen, halogen, -NH 2 , -CN, -OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, or (C1-C4)(C1-C4) dialkylamino.
  • each of R 5a , R 5b , R 5c , and R 5d is independently hydrogen, halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, or (C1-C4)(C1-C4) dialkylamino.
  • each of R 5a , R 5b , R 5c , and R 5d is independently hydrogen, -F, -Cl, -NH 2 , -CN, -OH, methyl, ethyl, n-propyl, i-propyl, -CH 2 F, -CH 2 Cl, - CH 2 CH 2 F, -CH 2 CH 2 Cl, -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CH 2 Cl, -CH(CH 3 )CH 2 F, - CH(CH 3 )CH 2 Cl, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH(CH 3 )CH 3 , -NHCH 3 , - NHCH 2 CH 3 , -NHCH 2 CH 2 CH 3 , -NHCH(CH 3 )CH 3 , -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 ,
  • each of R 5a , R 5b , R 5c , and R 5d is independently hydrogen, -F, -Cl, -NH 2 , -CN, -OH, methyl, ethyl, - CH 2 F, -CH 2 Cl, -CH 2 CH 2 F, -CH 2 CH 2 Cl, -OCH 3 , -OCH 2 CH 3 , -NHCH 3 , -NHCH 2 CH 3 , - N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , or -N(CH 3 )(CH 2 CH 3 ).
  • each of R 5a , R 5b , R 5c , and R 5d is independently hydrogen, -F, -Cl, -NH 2 , -CN, -OH, methyl, -CH 2 F, -CH 2 Cl, - OCH 3 , -NHCH 3 , or -N(CH 3 ) 2 .
  • each of R 5a , R 5b , and R 5d is independently hydrogen, -F, - Cl, -NH 2 , -CN, -OH, methyl, ethyl, n-propyl, i-propyl, -CH 2 F, -CH 2 Cl, -CH 2 CH 2 F, - CH 2 CH 2 Cl, -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CH 2 Cl, -CH(CH 3 )CH 2 F, -CH(CH 3 )CH 2 Cl, -OCH 3 , - OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH(CH 3 )CH 3 , -NHCH 3 , -NHCH 2 CH 3 , -NHCH 2 CH 2 CH 3 , - NHCH(CH 3 )CH 3 , -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , -N(CH 2 CH 3 ) 2
  • each of R 5a , R 5b , and R 5d is independently hydrogen, -F, -Cl, -NH 2 , -CN, -OH, methyl, ethyl, -CH 2 F, -CH 2 Cl, -CH 2 CH 2 F, - CH 2 CH 2 Cl, -OCH 3 , -OCH 2 CH 3 , -NHCH 3 , -NHCH 2 CH 3 , -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , - N(CH 3 )(CH 2 CH 3 ), or Cy 3 .
  • each of R 5a , R 5b , and R 5d is independently hydrogen, -F, -Cl, -NH 2 , -CN, -OH, methyl, -CH 2 F, -CH 2 Cl, -OCH 3 , -NHCH 3 , -N(CH 3 ) 2 , or Cy 3 .
  • each of R 5a , R 5b , and R 5d is independently hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, or (C1-C4)(C1-C4) dialkylamino, -CO 2 (C1-C4 alkyl), -CO 2 H, -CO 2 NH 2 , -NHC(O)Cy 3 , -NHC(O)(C1-C4 alkyl), or Cy 3 .
  • each of R 5a , R 5b , and R 5d is independently hydrogen, methyl, ethyl, n-propyl, i-propyl, -CH 2 F, -CH 2 Cl, -CH 2 CH 2 F, -CH 2 CH 2 Cl, -CH 2 CH 2 CH 2 F, - CH 2 CH 2 Cl, -CH(CH 3 )CH 2 F, -CH(CH 3 )CH 2 Cl, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , - OCH(CH 3 )CH 3 , -NHCH 3 , -NHCH 2 CH 3 , -NHCH 2 CH 2 CH 3 , -NHCH(CH 3 )CH 3 , -N(CH 3 ) 2 , - N(CH 2 CH 3 ) 2 , -N(CH 2 CH 2 CH 3 ) 2 , -N(CH(CH 3 )CH 3 )
  • each of R 5a , R 5b , and R 5d is independently hydrogen, methyl, ethyl, -CH 2 F, - CH 2 Cl, -CH 2 CH 2 F, -CH 2 CH 2 Cl, -OCH 3 , -OCH 2 CH 3 , -NHCH 3 , -NHCH 2 CH 3 , -N(CH 3 ) 2 , - N(CH 2 CH 3 ) 2 , -N(CH 3 )(CH 2 CH 3 ), -CO 2 CH 3 , -CO 2 CH 2 CH 3 , -CO 2 H, -CO 2 NH 2 , - NHC(O)Cy 3 , -NHC(O)CH 3 , -NHC(O)CH 2 CH 3 , or Cy 3 .
  • each of R 5a , R 5b , and R 5d is independently hydrogen, methyl, -CH 2 F, -CH 2 Cl, -OCH 3 , -NHCH 3 , - N(CH 3 ) 2 , -CO 2 CH 3 , -CO 2 H, -CO 2 NH 2 , -NHC(O)Cy 3 , -NHC(O)CH 3 , or Cy 3 .
  • each of R 5a , R 5b , and R 5d is independently hydrogen, -F, - Cl, -NH 2 , -CN, -OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, -CO 2 (C1-C4 alkyl), -CO 2 H, -CO 2 NH 2 , -NHC(O)Cy 3 , -NHC(O)(C1-C4 alkyl), or Cy 3 .
  • each of R 5a , R 5b , and R 5d is independently hydrogen, - F, -Cl, -NH 2 , -CN, -OH, methyl, ethyl, n -propyl, i -propyl, -OCH 3 , -OCH 2 CH 3 , - OCH 2 CH 2 CH 3 , -OCH(CH 3 )CH 3 , -NHCH 3 , -NHCH 2 CH 3 , -NHCH 2 CH 2 CH 3 , - NHCH(CH 3 )CH 3 , -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , -N(CH 2 CH 2 CH 3 ) 2 , -N(CH(CH 3 )CH 3 ) 2 , - N(CH 3 )(CH 2 CH 3 ), -CO 2 CH 3 , -CO 2 CH 2 CH 3 , -CO 2 CH 2 CH 3 , -CO 2 CH 2
  • each of R 5a , R 5b , and R 5d is independently hydrogen, -F, -Cl, -NH 2 , -CN, -OH, methyl, ethyl, -OCH 3 , -OCH 2 CH 3 , -NHCH 3 , - NHCH 2 CH 3 , -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , -N(CH 3 )(CH 2 CH 3 ), -CO 2 CH 3 , -CO 2 CH 2 CH 3 , - CO 2 H, -CO 2 NH 2 , -NHC(O)Cy 3 , -NHC(O)CH 3 , -NHC(O)CH 2 CH 3 , or Cy 3 .
  • each of R 5a , R 5b , and R 5d is independently hydrogen, -F, -Cl, -NH 2 , -CN, -OH, methyl, -OCH 3 , -NHCH 3 , -N(CH 3 ) 2 , -CO 2 CH 3 , -CO 2 H, -CO 2 NH 2 , -NHC(O)Cy 3 , - NHC(O)CH 3 , or Cy 3 .
  • each of R 5a , R 5b , and R 5d is independently hydrogen, -F, - Cl, -NH 2 , -CN, -OH, C1-C4 alkyl, C1-C4 alkoxy, -CO 2 (C1-C4 alkyl), -CO 2 H, -CO 2 NH 2 , - NHC(O)Cy 3 , -NHC(O)(C1-C4 alkyl), or Cy 3 .
  • each of R 5a , R 5b , and R 5d is independently hydrogen, -F, -Cl, -NH 2 , -CN, -OH, methyl, ethyl, n -propyl, i -propyl, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH(CH 3 )CH 3 , -CO 2 CH 3 , -CO 2 CH 2 CH 3 , - CO 2 CH 2 CH 2 CH 3 , -CO 2 CH(CH 3 ) 2 , -CO 2 H, -CO 2 NH 2 , -NHC(O)Cy 3 , -NHC(O)CH 3 , - NHC(O)CH 2 CH 3 , -NHC(O)CH 2 CH 2 CH 3 , -NHC(O)CH(CH 3 ) 2 , or Cy 3 .
  • each of R 5a , R 5b , and R 5d is independently hydrogen, -F, -Cl, -NH 2 , -CN, -OH, methyl, ethyl, -OCH 3 , -OCH 2 CH 3 , -CO 2 CH 3 , -CO 2 CH 2 CH 3 , -CO 2 H, -CO 2 NH 2 , - NHC(O)Cy 3 , -NHC(O)CH 3 , -NHC(O)CH 2 CH 3 , or Cy 3 .
  • each of R 5a , R 5b , and R 5d is independently hydrogen, -F, -Cl, -NH 2 , -CN, -OH, methyl, -OCH 3 , - CO 2 CH 3 , -CO 2 H, -CO 2 NH 2 , -NHC(O)Cy 3 , -NHC(O)CH 3 , or Cy 3 .
  • each of R 5a , R 5b , and R 5d is independently hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 alkoxy.
  • each of R 5a , R 5b , and R 5d is independently hydrogen, methyl, ethyl, n -propyl, i -propyl, -CH 2 F, -CH 2 Cl, -CH 2 CH 2 F, - CH 2 CH 2 Cl, -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CH 2 Cl, -CH(CH 3 )CH 2 F, -CH(CH 3 )CH 2 Cl, -OCH 3 , - OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , or -OCH(CH 3 )CH 3 .
  • each of R 5a , R 5b , and R 5d is independently hydrogen, methyl, ethyl, -CH 2 F, -CH 2 Cl, -CH 2 CH 2 F, -CH 2 CH 2 Cl, - OCH 3 , or -OCH 2 CH 3 .
  • each of R 5a , R 5b , and R 5d is independently hydrogen, methyl, -CH 2 F, -CH 2 Cl, or -OCH 3 .
  • each of R 5a , R 5b , and R 5d is independently hydrogen or Cy 3 .
  • each of R 5a , R 5b , and R 5d is independently hydrogen, - CO 2 (C1-C4 alkyl), -CO 2 H, -CO 2 NH 2 , -NHC(O)Cy 3 , or -NHC(O)(C 1-C4 alkyl).
  • each of R 5a , R 5b , and R 5d is independently hydrogen, -CO 2 CH 3 , -CO 2 CH 2 CH 3 , -CO 2 CH 2 CH 2 CH 3 , -CO 2 CH(CH 3 ) 2 , -CO 2 H, -CO 2 NH 2 , -NHC(O)Cy 3 , -NHC(O)CH 3 , - NHC(O)CH 2 CH 3 , -NHC(O)CH 2 CH 2 CH 3 , or -NHC(O)CH(CH 3 ) 2 .
  • each of R 5a , R 5b , and R 5d is independently hydrogen, -CO 2 CH 3 , -CO 2 CH 2 CH 3 , -CO 2 H, - CO 2 NH 2 , -NHC(O)Cy 3 , -NHC(O)CH 3 , or -NHC(O)CH 2 CH 3 .
  • each of R 5a , R 5b , and R 5d is independently hydrogen, -CO 2 CH 3 , -CO 2 H, -CO 2 NH 2 , - NHC(O)Cy 3 , or -NHC(O)CH 3 .
  • each of R 5a , R 5b , and R 5d is independently hydrogen or C1-C4 haloalkyl.
  • each of R 5a , R 5b , and R 5d is independently hydrogen, - CH 2 F, -CH 2 Cl, -CH 2 CH 2 F, -CH 2 CH 2 Cl, -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CH 2 Cl, -CH(CH 3 )CH 2 F, or -CH(CH 3 )CH 2 Cl.
  • each of R 5a , R 5b , and R 5d is independently hydrogen, -CH 2 F, -CH 2 Cl, -CH 2 CH 2 F, or -CH 2 CH 2 Cl. In yet a further aspect, each of R 5a , R 5b , and R 5d is independently hydrogen, -CH 2 F or -CH 2 Cl.
  • each of R 5a , R 5b , and R 5d is independently hydrogen or C1-C4 alkyl. In a still further aspect, each of R 5a , R 5b , and R 5d is independently hydrogen, methyl, ethyl, n -propyl, i -propyl, n -butyl, i -butyl, s -butyl, or t -butyl. In yet a further aspect, each of R 5a , R 5b , and R 5d is independently hydrogen, methyl, ethyl, n -propyl, or i -propyl.
  • each of R 5a , R 5b , and R 5d is independently hydrogen, methyl or ethyl. In a still further aspect, each of R 5a , R 5b , and R 5d is independently hydrogen or ethyl. In yet a further aspect, each of R 5a , R 5b , and R 5d is independently hydrogen or methyl.
  • each of R 5a , R 5b , and R 5d is independently hydrogen, halogen, -NH 2 , -CN, -OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, or (C1-C4)(C1-C4) dialkylamino.
  • each of R 5a , R 5b , and R 5d is independently hydrogen, - F, -Cl, -NH 2 , -CN, -OH, methyl, ethyl, n -propyl, i -propyl, -CH 2 F, -CH 2 Cl, -CH 2 CH 2 F, - CH 2 CH 2 Cl, -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CH 2 Cl, -CH(CH 3 )CH 2 F, -CH(CH 3 )CH 2 Cl, -OCH 3 , - OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH(CH 3 )CH 3 , -NHCH 3 , -NHCH 2 CH 3 , -NHCH 2 CH 2 CH 3 , - NHCH(CH 3 )CH 3 , -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , -N(CH 2 CH 3
  • each of R 5a , R 5b , and R 5d is independently hydrogen, -F, -Cl, -NH 2 , -CN, -OH, methyl, ethyl, -CH 2 F, -CH 2 Cl, -CH 2 CH 2 F, - CH 2 CH 2 Cl, -OCH 3 , -OCH 2 CH 3 , -NHCH 3 , -NHCH 2 CH 3 , -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , or - N(CH 3 )(CH 2 CH 3 ).
  • each of R 5a , R 5b , and R 5d is independently hydrogen, -F, -Cl, -NH 2 , -CN, -OH, methyl, -CH 2 F, -CH 2 Cl, -OCH 3 , -NHCH 3 , or - N(CH 3 ) 2 .
  • R 5b is fluorine
  • R 5c is hydrogen, halogen, -NH 2 , -CN, -OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, or (C1-C4)(C1-C4) dialkylamino.
  • R 5c is hydrogen, halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, or (C1-C4)(C1-C4) dialkylamino.
  • R 5c is hydrogen, halogen, -NH 2 , -OH, - C1-C4 alkoxy, C1-C4 alkylamino, or (C1-C4)(C1-C4) dialkylamino.
  • R 5c is hydrogen, -F, -Cl, -NH 2 , -OH, methyl, ethyl, n -propyl, i -propyl, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH(CH 3 )CH 3 , -NHCH 3 , -NHCH 2 CH 3 , -NHCH 2 CH 2 CH 3 , - NHCH(CH 3 )CH 3 , -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , -N(CH 2 CH 2 CH 3 ) 2 , -N(CH(CH 3 )CH 3 ) 2 , or - N(CH 3 )(CH 2 CH 3 ).
  • R 5c is hydrogen, -F, -Cl, -NH 2 , -CN, -OH, methyl, ethyl, -OCH 3 , -OCH 2 CH 3 , -NHCH 3 , -NHCH 2 CH 3 , -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , or - N(CH 3 )(CH 2 CH 3 ).
  • R 5c is hydrogen, -F, -Cl, -NH 2 , -CN, -OH, methyl, -OCH 3 , -NHCH 3 , or -N(CH 3 ) 2 .
  • R 5c is hydrogen, -F, -NH 2 , -CN, -OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, or (C1-C4)(C1-C4) dialkylamino.
  • R 5c is hydrogen, -F, -NH 2 , -CN, -OH, methyl, ethyl, n -propyl, i -propyl, -OCH 3 , -OCH 2 CH 3 , - OCH 2 CH 2 CH 3 , -OCH(CH 3 )CH 3 , -NHCH 3 , -NHCH 2 CH 3 , -NHCH 2 CH 2 CH 3 , - NHCH(CH 3 )CH 3 , -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , -N(CH 2 CH 2 CH 3 ) 2 , -N(CH(CH 3 )CH 3 ) 2 , or - N(CH 3 )(CH 2 CH 3 ).
  • R 5c is hydrogen, -F, -NH 2 , -CN, -OH, methyl, ethyl, -OCH 3 , -OCH 2 CH 3 , -NHCH 3 , -NHCH 2 CH 3 , -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , or - N(CH 3 )(CH 2 CH 3 ).
  • R 5c is hydrogen, -F, -NH 2 , -CN, -OH, methyl, - OCH 3 , -NHCH 3 , or -N(CH 3 ) 2 .
  • R 5c is halogen, -NH 2 , -CN, -OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, or (C1-C4)(C1-C4) dialkylamino.
  • R 5c is -F, -Cl, -NH 2 , -CN, -OH, methyl, ethyl, n -propyl, i -propyl, -OCH 3 , -OCH 2 CH 3 , - OCH 2 CH 2 CH 3 , -OCH(CH 3 )CH 3 , -NHCH 3 , -NHCH 2 CH 3 , -NHCH 2 CH 2 CH 3 , - NHCH(CH 3 )CH 3 , -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , -N(CH 2 CH 2 CH 3 ) 2 , -N(CH(CH 3 )CH 3 ) 2 , or - N(CH 3 )(CH 2 CH 3 ).
  • R 5c is -F, -Cl, -NH 2 , -CN, -OH, methyl, ethyl, - OCH 3 , -OCH 2 CH 3 , -NHCH 3 , -NHCH 2 CH 3 , -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , or - N(CH 3 )(CH 2 CH 3 ).
  • R 5c is -F, -Cl, -NH 2 , -CN, -OH, methyl, -OCH 3 , -NHCH 3 , or -N(CH 3 ) 2 .
  • R 5c is -F, -NH 2 , -CN, -OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, or (C1-C4)(C1-C4) dialkylamino.
  • R 5c is -F, - NH 2 , -CN, -OH, methyl, ethyl, n-propyl, i-propyl, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , - OCH(CH 3 )CH 3 , -NHCH 3 , -NHCH 2 CH 3 , -NHCH 2 CH 2 CH 3 , -NHCH(CH 3 )CH 3 , -N(CH 3 ) 2 , - N(CH 2 CH 3 ) 2 , -N(CH 2 CH 2 CH 3 ) 2 , -N(CH(CH 3 )CH 3 ) 2 , or -N(CH 3 )(CH 2 CH 3 ).
  • R 5c is -F, -NH 2 , -CN, -OH, methyl, ethyl, -OCH 3 , -OCH 2 CH 3 , -NHCH 3 , - NHCH 2 CH 3 , -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , or -N(CH 3 )(CH 2 CH 3 ).
  • R 5c is -F, -NH 2 , -CN, -OH, methyl, -OCH 3 , -NHCH 3 , or -N(CH 3 ) 2 .
  • R 5c is hydrogen, halogen, -NH 2 , -OH, -CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, -CO 2 (C1-C4 alkyl), -CO 2 H, -CO 2 NH 2 , -NHC(O)Cy 3 , -NHC(O)(C1-C4 alkyl), or aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, - NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • R 5c is fluorine
  • R 6a is hydrogen or C1-C4 alkyl. In a further aspect, R 6a is hydrogen.
  • R 6a is hydrogen, methyl, ethyl, isopropyl, n-propyl, isobutyl, n-butyl, s-butyl, or t-butyl. In a still further aspect, R 6a is hydrogen, methyl, ethyl, isopropyl, or n-propyl. In yet a further aspect, R 6a is hydrogen, methyl, or ethyl. In an even further aspect, R 6a is hydrogen or methyl. In a still further aspect, R 6a is hydrogen or ethyl.
  • R 6a is methyl, ethyl, isopropyl, n-propyl, isobutyl, n-butyl, s-butyl, or t-butyl. In a still further aspect, R 6a is methyl, ethyl, isopropyl, or n-propyl. In yet a further aspect, R 6a is methyl, or ethyl. In an even further aspect, R 6a is methyl. In a still further aspect, R 6a is ethyl.
  • R 6b is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, or -CO 2 H. In a further aspect, R 6b is -CO 2 H.
  • R 6b is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, or (C1-C4)(C1-C4) dialkylamino. In a further aspect, R 6b is hydrogen.
  • R 6b is hydrogen, methyl, ethyl, n -propyl, i -propyl, -CH 2 F, -CH 2 Cl, -CH 2 CH 2 F, -CH 2 CH 2 Cl, -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CH 2 Cl, -CH(CH 3 )CH 2 F, - CH(CH 3 )CH 2 Cl, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH(CH 3 )CH 3 , -NHCH 3 , - NHCH 2 CH 3 , -NHCH 2 CH 2 CH 3 , -NHCH(CH 3 )CH 3 , -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , - N(CH 2 CH 2 CH 3 ) 2 , -N(CH(CH 3 )CH 3 ) 2 , or -N(CH 3 )
  • R 6b is hydrogen, methyl, ethyl, -CH 2 F, -CH 2 Cl, -CH 2 CH 2 F, -CH 2 CH 2 Cl, -OCH 3 , -OCH 2 CH 3 , - NHCH 3 , -NHCH 2 CH 3 , -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , or -N(CH 3 )(CH 2 CH 3 ).
  • R 6b is hydrogen, methyl, -CH 2 F, -CH 2 Cl, -OCH 3 , -NHCH 3 , or -N(CH 3 ) 2 .
  • R 6b is hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, or (C1-C4)(C1-C4) dialkylamino.
  • R 6b is hydrogen, methyl, ethyl, n -propyl, i -propyl, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH(CH 3 )CH 3 , - NHCH 3 , -NHCH 2 CH 3 , -NHCH 2 CH 2 CH 3 , -NHCH(CH 3 )CH 3 , -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , -N(CH(CH 3 )CH 3 ) 2 , or -N(CH 3 )(CH 2 CH 3 ).
  • R 6b is hydrogen, methyl, ethyl, -OCH 3 , -OCH 2 CH 3 , -NHCH 3 , -NHCH 2 CH 3 , -N(CH 3 ) 2 , - N(CH 2 CH 3 ) 2 , or -N(CH 3 )(CH 2 CH 3 ).
  • R 6b is hydrogen, methyl, - OCH 3 , -NHCH 3 , or -N(CH 3 ) 2 .
  • R 6b is hydrogen, C1-C4 alkyl, or C1-C4 alkoxy.
  • R 6b is hydrogen, methyl, ethyl, n -propyl, i -propyl, -OCH 3 , -OCH 2 CH 3 , - OCH 2 CH 2 CH 3 , or -OCH(CH 3 )CH 3 .
  • R 6b is hydrogen, methyl, ethyl, - OCH 3 , or -OCH 2 CH 3 .
  • R 6b is hydrogen, methyl, or -OCH 3 .
  • R 6b is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 alkoxy.
  • R 6b is hydrogen, methyl, ethyl, n -propyl, i -propyl, -CH 2 F, - CH 2 Cl, -CH 2 CH 2 F, -CH 2 CH 2 Cl, -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CH 2 Cl, -CH(CH 3 )CH 2 F, - CH(CH 3 )CH 2 Cl, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , or -OCH(CH 3 )CH 3 .
  • R 6b is hydrogen, methyl, ethyl, -CH 2 F, -CH 2 Cl, -CH 2 CH 2 F, -CH 2 CH 2 Cl, -OCH 3 , or -OCH 2 CH 3 . In yet a further aspect, R 6b is hydrogen, methyl, -CH 2 F, -CH 2 Cl, or -OCH 3 .
  • R 6b is C1-C4 alkyl. In a still further aspect, R 6b is methyl, ethyl, n -propyl, i -propyl, n -butyl, i -butyl, s -butyl, or t -butyl. In yet a further aspect, R 6b is methyl, ethyl, n -propyl, or i -propyl. In an even further aspect, R 6b is methyl or ethyl. In a still further aspect, R 6b is ethyl. In yet a further aspect, R 6b is methyl.
  • R 7 is hydrogen, halogen, -OH, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 alkoxy. In a further aspect, R 7 is hydrogen.
  • R 7 is hydrogen, -F, -Cl, -OH, methyl, ethyl, n -propyl, i- propyl, -CH 2 F, -CH 2 Cl, -CH 2 CH 2 F, -CH 2 CH 2 Cl, -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CH 2 Cl, - CH(CH 3 )CH 2 F, -CH(CH 3 )CH 2 Cl, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , or -OCH(CH 3 )CH 3 .
  • R 7 is hydrogen, -F, -Cl, -OH, methyl, ethyl, -CH 2 F, -CH 2 Cl, - CH 2 CH 2 F, -CH 2 CH 2 Cl, -OCH 3 , or -OCH 2 CH 3 .
  • R 7 is hydrogen, -F, - Cl, -OH, methyl, -CH 2 F, -CH 2 Cl, or -OCH 3 .
  • R 7 is hydrogen, -F, -Cl, -OH, C1-C4 alkyl, or C1-C4 alkoxy.
  • R 7 is hydrogen, -F, -Cl, -OH, methyl, ethyl, n -propyl, i- propyl, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , or -OCH(CH 3 )CH 3 .
  • R 7 is hydrogen, -F, -Cl, -OH, methyl, ethyl, -OCH 3 , or -OCH 2 CH 3 .
  • R 7 is hydrogen, -F, -Cl, -OH, methyl, or -OCH 3 .
  • R 7 is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 alkoxy.
  • R 7 is hydrogen, methyl, ethyl, n -propyl, i -propyl, -CH 2 F, - CH 2 Cl, -CH 2 CH 2 F, -CH 2 CH 2 Cl, -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CH 2 Cl, -CH(CH 3 )CH 2 F, - CH(CH 3 )CH 2 Cl, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , or -OCH(CH 3 )CH 3 .
  • R 7 is hydrogen, methyl, ethyl, -CH 2 F, -CH 2 Cl, -CH 2 CH 2 F, -CH 2 CH 2 Cl, -OCH 3 , or - OCH 2 CH 3 . In yet a further aspect, R 7 is hydrogen, methyl, -CH 2 F, -CH 2 Cl, or -OCH 3 .
  • R 7 is C1-C4 alkyl. In a still further aspect, R 7 is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl. In yet a further aspect, R 7 is methyl, ethyl, n-propyl, or i-propyl. In an even further aspect, R 7 is methyl or ethyl. In a still further aspect, R 7 is ethyl. In yet a further aspect, R 7 is methyl.
  • R 8 is hydrogen, C1-C4 alkyl, or C1-C4 haloalkyl. In a further aspect, R 8 is hydrogen.
  • R 8 is hydrogen, methyl, ethyl, n-propyl, i-propyl, -CH 2 F, - CH 2 Cl, -CH 2 CH 2 F, -CH 2 CH 2 Cl, -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CH 2 Cl, -CH(CH 3 )CH 2 F, or - CH(CH 3 )CH 2 Cl.
  • R 8 is hydrogen, methyl, ethyl, -CH 2 F, -CH 2 Cl, - CH 2 CH 2 F, or -CH 2 CH 2 Cl.
  • R 8 is hydrogen, methyl, -CH 2 F, or - CH 2 Cl.
  • R 8 is hydrogen or C1-C4 alkyl. In a still further aspect, R 8 is hydrogen, methyl, ethyl, n -propyl, or i -propyl. In a still further aspect, R 8 is hydrogen, methyl, or ethyl. In yet a further aspect, R 8 is hydrogen or ethyl. In an even further aspect, R 8 is hydrogen or methyl.
  • R 8 is hydrogen or C1-C4 haloalkyl.
  • R 8 is hydrogen, -CH 2 F, -CH 2 Cl, -CH 2 CH 2 F, -CH 2 CH 2 Cl, -CH 2 CH 2 CH 2 F, - CH 2 CH 2 Cl, -CH(CH 3 )CH 2 F, or -CH(CH 3 )CH 2 Cl.
  • R 8 is hydrogen, -CH 2 F, -CH 2 Cl, -CH 2 CH 2 F, or -CH 2 CH 2 Cl.
  • R 8 is hydrogen, -CH 2 F, or -CH 2 Cl.
  • R 8 is C1-C4 haloalkyl.
  • R 8 is - CH 2 F, -CH 2 Cl, -CH 2 CH 2 F, -CH 2 CH 2 Cl, -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CH 2 Cl, -CH(CH 3 )CH 2 F, or -CH(CH 3 )CH 2 Cl.
  • R 8 is -CH 2 F, -CH 2 Cl, -CH 2 CH 2 F, or - CH 2 CH 2 Cl.
  • R 8 is -CH 2 F or -CH 2 Cl.
  • R 8 is C1-C4 alkyl. In a still further aspect, R 8 is methyl, ethyl, n -propyl, i -propyl, n -butyl, i -butyl, s -butyl, or t -butyl. In yet a further aspect, R 8 is methyl, ethyl, n -propyl, or i -propyl. In an even further aspect, R 8 is methyl or ethyl. In a still further aspect, R 8 is ethyl. In yet a further aspect, R 8 is methyl.
  • R 8a when present, is C1-C4 alkyl. In a still further aspect, R 8a , when present, is methyl, ethyl, n -propyl, i -propyl, n -butyl, i -butyl, s -butyl, or t -butyl. In yet a further aspect, R 8a , when present, is methyl, ethyl, n -propyl, or i -propyl. In an even further aspect, R 8a , when present, is methyl or ethyl. In a still further aspect, R 8a , when present, is ethyl. In yet a further aspect, R 8a , when present, is methyl.
  • R 8b when present, is C1-C4 alkyl. In a still further aspect, R 8b , when present, is methyl, ethyl, n -propyl, i -propyl, n -butyl, i -butyl, s -butyl, or t -butyl. In yet a further aspect, R 8b , when present, is methyl, ethyl, n -propyl, or i -propyl. In an even further aspect, R 8b , when present, is methyl or ethyl. In a still further aspect, R 8b , when present, is ethyl. In yet a further aspect, R 8b , when present, is methyl.
  • R 8a when present, is C1-C4 haloalkyl.
  • R 8a when present, is -CH 2 F, -CH 2 Cl, -CH 2 CH 2 F, -CH 2 CH 2 Cl, -CH 2 CH 2 CH 2 F, - CH 2 CH 2 CH 2 Cl, -CH(CH 3 )CH 2 F, or -CH(CH 3 )CH 2 Cl.
  • R 8a when present, is -CH 2 F, -CH 2 Cl, -CH 2 CH 2 F, or -CH 2 CH 2 Cl.
  • R 8a when present, is -CH 2 F or -CH 2 Cl.
  • R 8b when present, is C1-C4 haloalkyl.
  • R 8b when present, is -CH 2 F, -CH 2 Cl, -CH 2 CH 2 F, -CH 2 CH 2 Cl, -CH 2 CH 2 CH 2 F, - CH 2 CH 2 CH 2 Cl, -CH(CH 3 )CH 2 F, or -CH(CH 3 )CH 2 Cl.
  • R 8b when present, is -CH 2 F, -CH 2 Cl, -CH 2 CH 2 F, or -CH 2 CH 2 Cl.
  • R 8b when present, is -CH 2 F or -CH 2 Cl.
  • R 8a is phenyl.
  • R 8a is phenyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • R 8a when present, is phenyl substituted with 0, 1, or 2 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • R 8a when present, is phenyl substituted with 0 or 1 group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • R 8a when present, is phenyl monosubstituted with a group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • R 8a when present, is unsubstituted phenyl.
  • R 8b is phenyl.
  • R 8b is phenyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • R 8b when present, is phenyl substituted with 0, 1, or 2 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • R 8b when present, is phenyl substituted with 0 or 1 group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • R 8b when present, is phenyl monosubstituted with a group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • R 8b when present, is unsubstituted phenyl.
  • R 8a when present, is -CO 2 H.
  • R 8b when present, is -CO 2 H.
  • R 9 is hydrogen, C1-C4 alkyl, or Cy 4 . In a further aspect, R 9 is hydrogen.
  • R 9 is C1-C4 alkyl. In a still further aspect, R 9 is methyl, ethyl, n -propyl, i -propyl, n -butyl, i -butyl, s -butyl, or t -butyl. In yet a further aspect, R 9 is methyl, ethyl, n -propyl, or i -propyl. In an even further aspect, R 8 is methyl or ethyl. In a still further aspect, R 9 is ethyl. In yet a further aspect, R 9 is methyl.
  • R 9 is Cy 4 .
  • Cy 1 when present, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 1 when present, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0, 1, or 2 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 1 when present, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0 or 1 group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 1 when present, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is monosubstituted with a group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 1 when present, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is unsubstituted.
  • Cy 1 when present, is C3-C6 cycloalkyl or C2-C5 heterocycloalkyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 1 when present, is C3-C6 cycloalkyl or C2-C5 heterocycloalkyl, and is substituted with 0, 1, or 2 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 1 when present, is C3-C6 cycloalkyl or C2-C5 heterocycloalkyl, and is substituted with 0 or 1 group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 1 when present, is C3-C6 cycloalkyl or C2-C5 heterocycloalkyl, and is monosubstituted with a group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 1 when present, is C3-C6 cycloalkyl or C2-C5 heterocycloalkyl, and is unsubstituted.
  • Cy 1 when present, is C3-C6 cycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 1 when present, is C3-C6 cycloalkyl substituted with 0, 1, or 2 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 1 when present, is C3-C6 cycloalkyl substituted with 0 or 1 group selected from halogen, - NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 1 when present, is C3-C6 cycloalkyl monosubstituted with a group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 1 when present, is unsubstituted C3-C6 cycloalkyl.
  • Cy 1 when present, is cyclopropyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 1 when present, is cyclopropyl substituted with 0, 1, or 2 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 1 when present, is cyclopropyl substituted with 0 or 1 group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 1 when present, is cyclopropyl monosubstituted with a group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 1 when present, is unsubstituted cyclopropyl.
  • Cy 1 when present, is C2-C5 heterocycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 1 when present, is C2-C5 heterocycloalkyl substituted with 0, 1, or 2 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 1 when present, is C2-C5 heterocycloalkyl substituted with 0 or 1 group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 1 when present, is C2-C5 heterocycloalkyl monosubstituted with a group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 1 when present, is unsubstituted C2-C5 heterocycloalkyl.
  • Cy 1 when present, is morpholinyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 1 when present, is morpholinyl substituted with 0, 1, or 2 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 1 when present, is morpholinyl substituted with 0 or 1 group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 1 when present, is morpholinyl monosubstituted with a group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 1 when present, is unsubstituted morpholinyl.
  • Cy 1 when present, is aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 1 when present, is aryl substituted with 0, 1, or 2 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 1 when present, is aryl substituted with 0 or 1 group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 1 when present, is aryl monosubstituted with a group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 1 when present, is unsubstituted aryl.
  • Cy 1 when present, is phenyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 1 when present, is phenyl substituted with 0, 1, or 2 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 1 when present, is phenyl substituted with 0 or 1 group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 1 when present, is phenyl monosubstituted with a group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 1 when present, is unsubstituted phenyl.
  • Cy 2 when present, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 2 when present, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0, 1, or 2 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 2 when present, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0 or 1 group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 2 when present, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is monosubstituted with a group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 2 when present, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is unsubstituted.
  • Cy 2 when present, is C3-C6 cycloalkyl or C2-C5 heterocycloalkyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 2 when present, is C3-C6 cycloalkyl or C2-C5 heterocycloalkyl, and is substituted with 0, 1, or 2 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 2 when present, is C3-C6 cycloalkyl or C2-C5 heterocycloalkyl, and is substituted with 0 or 1 group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 2 when present, is C3-C6 cycloalkyl or C2-C5 heterocycloalkyl, and is monosubstituted with a group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 2 when present, is C3-C6 cycloalkyl or C2-C5 heterocycloalkyl, and is unsubstituted.
  • Cy 2 when present, is C3-C6 cycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 2 when present, is C3-C6 cycloalkyl substituted with 0, 1, or 2 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 2 when present, is C3-C6 cycloalkyl substituted with 0 or 1 group selected from halogen, - NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 2 when present, is C3-C6 cycloalkyl monosubstituted with a group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 2 when present, is unsubstituted C3-C6 cycloalkyl.
  • Cy 2 when present, is cyclopropyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 2 when present, is cyclopropyl substituted with 0, 1, or 2 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 2 when present, is cyclopropyl substituted with 0 or 1 group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 2 when present, is cyclopropyl monosubstituted with a group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 2 when present, is unsubstituted cyclopropyl.
  • Cy 2 when present, is C2-C5 heterocycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 2 when present, is C2-C5 heterocycloalkyl substituted with 0, 1, or 2 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 2 when present, is C2-C5 heterocycloalkyl substituted with 0 or 1 group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 2 when present, is C2-C5 heterocycloalkyl monosubstituted with a group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 2 when present, is unsubstituted C2-C5 heterocycloalkyl.
  • Cy 2 when present, is aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 2 when present, is aryl substituted with 0, 1, or 2 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 2 when present, is aryl substituted with 0 or 1 group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 2 when present, is aryl monosubstituted with a group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 2 when present, is unsubstituted aryl.
  • Cy 2 when present, is phenyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 2 when present, is phenyl substituted with 0, 1, or 2 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 2 when present, is phenyl substituted with 0 or 1 group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 2 when present, is phenyl monosubstituted with a group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 2 when present, is unsubstituted phenyl.
  • Cy 3 when present, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 3 when present, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0, 1, or 2 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 3 when present, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0 or 1 group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 3 when present, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is monosubstituted with a group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 3 when present, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is unsubstituted.
  • Cy 3 when present, is C3-C6 cycloalkyl or C2-C5 heterocycloalkyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 3 when present, is C3-C6 cycloalkyl or C2-C5 heterocycloalkyl, and is substituted with 0, 1, or 2 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 3 when present, is C3-C6 cycloalkyl or C2-C5 heterocycloalkyl, and is substituted with 0 or 1 group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 3 when present, is C3-C6 cycloalkyl or C2-C5 heterocycloalkyl, and is monosubstituted with a group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 3 when present, is C3-C6 cycloalkyl or C2-C5 heterocycloalkyl, and is unsubstituted.
  • Cy 3 when present, is C3-C6 cycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 3 when present, is C3-C6 cycloalkyl substituted with 0, 1, or 2 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 3 when present, is C3-C6 cycloalkyl substituted with 0 or 1 group selected from halogen, - NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 3 when present, is C3-C6 cycloalkyl monosubstituted with a group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 3 when present, is unsubstituted C3-C6 cycloalkyl.
  • Cy 3 when present, is C2-C5 heterocycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 3 when present, is C2-C5 heterocycloalkyl substituted with 0, 1, or 2 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 3 when present, is C2-C5 heterocycloalkyl substituted with 0 or 1 group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 3 when present, is C2-C5 heterocycloalkyl monosubstituted with a group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 3 when present, is unsubstituted C2-C5 heterocycloalkyl.
  • Cy 3 when present, is morpholinyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 3 when present, is morpholinyl substituted with 0, 1, or 2 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 3 when present, is morpholinyl substituted with 0 or 1 group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 3 when present, is morpholinyl monosubstituted with a group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 3 when present, is unsubstituted morpholinyl.
  • Cy 3 when present, is aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 3 when present, is aryl substituted with 0, 1, or 2 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 3 when present, is aryl substituted with 0 or 1 group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 3 when present, is aryl monosubstituted with a group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 3 when present, is unsubstituted aryl.
  • Cy 3 when present, is phenyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 3 when present, is phenyl substituted with 0, 1, or 2 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 3 when present, is phenyl substituted with 0 or 1 group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 3 when present, is phenyl monosubstituted with a group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 3 when present, is unsubstituted phenyl.
  • Cy 3 when present, is pyridinyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 3 when present, is pyridinyl substituted with 0, 1, or 2 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 3 when present, is pyridinyl substituted with 0 or 1 group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 3 when present, is pyridinyl monosubstituted with a group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 3 when present, is unsubstituted pyridinyl.
  • Cy 3 when present, is oxazolyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 3 when present, is oxazolyl substituted with 0, 1, or 2 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 3 when present, is oxazolyl substituted with 0 or 1 group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 3 when present, is oxazolyl monosubstituted with a group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 3 when present, is unsubstituted oxazolyl.
  • Cy 3 when present, is C3-C6 cycloalkyl or aryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 3 when present, is C3-C6 cycloalkyl or aryl, and is substituted with 0, 1, or 2 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 3 when present, is C3-C6 cycloalkyl or aryl, and is substituted with 0 or 1 group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 3 when present, is C3-C6 cycloalkyl or aryl, and is monosubstituted with a group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 3 when present, is C3-C6 cycloalkyl or aryl, and is unsubstituted.
  • Cy 4 when present, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 4 when present, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0, 1, or 2 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 4 when present, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0 or 1 group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 4 when present, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is monosubstituted with a group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 4 when present, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is unsubstituted.
  • Cy 4 when present, is C3-C6 cycloalkyl or C2-C5 heterocycloalkyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 4 when present, is C3-C6 cycloalkyl or C2-C5 heterocycloalkyl, and is substituted with 0, 1, or 2 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 4 when present, is C3-C6 cycloalkyl or C2-C5 heterocycloalkyl, and is substituted with 0 or 1 group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 4 when present, is C3-C6 cycloalkyl or C2-C5 heterocycloalkyl, and is monosubstituted with a group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 4 when present, is C3-C6 cycloalkyl or C2-C5 heterocycloalkyl, and is unsubstituted.
  • Cy 4 when present, is C3-C6 cycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 4 when present, is C3-C6 cycloalkyl substituted with 0, 1, or 2 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 4 when present, is C3-C6 cycloalkyl substituted with 0 or 1 group selected from halogen, - NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 4 when present, is C3-C6 cycloalkyl monosubstituted with a group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 4 when present, is unsubstituted C3-C6 cycloalkyl.
  • Cy 4 when present, is cyclopropyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 4 when present, is cyclopropyl substituted with 0, 1, or 2 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 4 when present, is cyclopropyl substituted with 0 or 1 group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 4 when present, is cyclopropyl monosubstituted with a group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 4 when present, is unsubstituted cyclopropyl.
  • Cy 4 when present, is C2-C5 heterocycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 4 when present, is C2-C5 heterocycloalkyl substituted with 0, 1, or 2 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 4 when present, is C2-C5 heterocycloalkyl substituted with 0 or 1 group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 4 when present, is C2-C5 heterocycloalkyl monosubstituted with a group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 4 when present, is unsubstituted C2-C5 heterocycloalkyl.
  • Cy 4 when present, is morpholinyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 4 when present, is morpholinyl substituted with 0, 1, or 2 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 4 when present, is morpholinyl substituted with 0 or 1 group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 4 when present, is morpholinyl monosubstituted with a group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 4 when present, is unsubstituted morpholinyl.
  • Cy 4 when present, is aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 4 when present, is aryl substituted with 0, 1, or 2 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 4 when present, is aryl substituted with 0 or 1 group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 4 when present, is aryl monosubstituted with a group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 4 when present, is unsubstituted aryl.
  • Cy 4 when present, is phenyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 4 when present, is phenyl substituted with 0, 1, or 2 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 4 when present, is phenyl substituted with 0 or 1 group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 4 when present, is phenyl monosubstituted with a group selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.
  • Cy 4 when present, is unsubstituted phenyl.
  • a compound in one aspect, can be present as one or more of the following structures: or a pharmaceutically acceptable salt thereof.
  • a compound in one aspect, can be present as the following structures: or a pharmaceutically acceptable salt thereof.
  • a compound in one aspect, can be present as one or more of the following structures: or a pharmaceutically acceptable salt thereof.
  • a compound in one aspect, can be present as one or more of the following structures: or a pharmaceutically acceptable salt thereof.
  • a compound in one aspect, can be present as one or more of the following structures: or a pharmaceutically acceptable salt thereof.
  • a compound in one aspect, can be present as one or more of the following structures: or a pharmaceutically acceptable salt thereof.
  • a compound in one aspect, can be present as one or more of the following structures: or a pharmaceutically acceptable salt thereof.
  • a compound in one aspect, can be selected from: or a subgroup thereof.
  • one or more compounds can optionally be omitted from the disclosed invention.
  • pharmaceutical acceptable derivatives of the disclosed compounds can be used also in connection with the disclosed methods, compositions, kits, and uses.
  • the pharmaceutical acceptable derivatives of the compounds can include any suitable derivative, such as pharmaceutically acceptable salts as discussed below, isomers, radiolabeled analogs, tautomers, and the like.
  • the compounds of this invention can be prepared by employing reactions as shown in the following schemes, in addition to other standard manipulations that are known in the literature, exemplified in the experimental sections or clear to one skilled in the art. For clarity, examples having a single substituent are shown where multiple substituents are allowed under the definitions disclosed herein.
  • Reactions used to generate the compounds of this invention are prepared by employing reactions as shown in the following Reaction Schemes, as described and exemplified below.
  • the disclosed compounds can be prepared by Routes I-IX, as described and exemplified below.
  • the following examples are provided so that the invention might be more fully understood, are illustrative only, and should not be construed as limiting.
  • substituted quinazoline sulfonamides can be prepared as shown below.
  • compounds of type 1.6 can be prepared according to reaction Scheme 1B above.
  • compounds of type 1.3 can be prepared by a sulfonylation reaction of an appropriate amine, e.g., 1.1 as shown above, and an appropriate sulfonyl halide, e.g., 1.2 as shown above.
  • Appropriate amines and appropriate sulfonyl halides are commercially available or prepared by methods known to one skilled in the art. In certain cases, a sulfonyl anhydride can also be used.
  • the sulfonylation reaction is carried out in the presence of an appropriate base, e.g., triethylamine (TEA), in an appropriate solvent, e.g., dichloromethane (DCM), for an appropriate period of time, e.g., 2 hours.
  • an appropriate base e.g., triethylamine (TEA)
  • DCM dichloromethane
  • Compounds of type 1.4 can be prepared by a deprotection reaction of an appropriate protected amine, e.g., 1.3 as shown above.
  • the deprotection reaction is carried out in the presence of an appropriate deprotecting agent, e.g., hydrochloric acid (HCl) as shown above, in an appropriate solvent, e.g., dioxane, for an appropriate period of time, e.g., 3 hours.
  • an appropriate deprotecting agent e.g., hydrochloric acid (HCl) as shown above
  • HCl hydrochloric acid
  • Compounds of type 1.6 can be prepared by a coupling reaction of an appropriate quinazoline derivative, e.g., 1.5 as shown above, and an appropriate amine, e.g., 1.4 as shown above.
  • Appropriate quinazoline derivatives are commercially available or prepared by methods known to one skilled in the art.
  • the coupling reaction is carried out in the presence of an appropriate base, e.g., N,N-diisopropylethylamine (DIPEA) or triethylamine, in an appropriate solvent, e.g., tetrahydrofuran (THF) or N-methyl-2-pyrrolidone.
  • DIPEA N,N-diisopropylethylamine
  • THF tetrahydrofuran
  • N-methyl-2-pyrrolidone N-methyl-2-pyrrolidone
  • the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactants above (compounds similar to compounds of type 1.7, 1.8, 1.9, 1.10, and 1.11), can be substituted in the reaction to provide substituted quinazoline sulfonamides similar to Formula 1.12.
  • substituted quinazoline sulfonamides can be prepared as shown below.
  • compounds of type 1.6 can be prepared according to reaction Schemes 2B, 2C, and 2D above.
  • compounds of type 2.2 can be prepared by a coupling reaction of an appropriate quinazoline derivative, e.g., 2.1 as shown above, and an appropriate amine, e.g., 1.4 as shown above.
  • Appropriate quinazoline derivatives and appropriate amines are commercially available or prepared by methods known to one skilled in the art.
  • the coupling reaction is carried out in the presence of an appropriate base, e.g., triethylamine, in an appropriate solvent, e.g., methanol, at an appropriate temperature, e.g., 50 °C, for an appropriate period of time, e.g., 4 hours.
  • an appropriate base e.g., triethylamine
  • an appropriate solvent e.g., methanol
  • an appropriate temperature e.g., 50 °C
  • an appropriate temperature e.g., 50 °C
  • an appropriate period of time e.g., 4 hours.
  • compounds of type 1.6 can be prepared by a Grignard reaction of an appropriate halide, e.g., 2.2 as shown above, and an appropriate Grignard reagent, e.g., 2.3 as shown above.
  • Appropriate Grignard reagents are commercially available or prepared by methods known to one skilled in the art.
  • the Grignard reaction is carried out in the presence of an appropriate metal salt, e.g., zinc chloride, and an appropriate catalyst, e.g., [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium, in an appropriate solvent, e.g., 1,4-dioxane, for an appropriate period of time, e.g., 16 hours.
  • an appropriate metal salt e.g., zinc chloride
  • an appropriate catalyst e.g., [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium
  • an appropriate solvent e.g., 1,4-dioxane
  • compounds of type 1.6 can be prepared by a coupling reaction of an appropriate halide, e.g., 2.2 as shown above, and an appropriate amine, e.g., 2.4 as shown above.
  • Appropriate amines are commercially available or prepared by methods known to one skilled in the
  • the coupling reaction is carried out in the presence of an appropriate base, e.g., potassium carbonate, in an appropriate solvent, e.g., 1,4-dioxane, at an appropriate temperature, e.g., 100 °C, for an appropriate period of time, e.g., 2 hours.
  • an appropriate temperature e.g., 90 °C
  • an appropriate period of time e.g., 2 hours.
  • the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactants above (compounds similar to compounds of type 1.10, 2.5, 2.6, 2.7, 2.9, and 2.11 ), can be substituted in the reaction to provide substituted quinazoline sulfonamides similar to Formulas 2.8, 2.10, and 2.12.
  • substituted quinazoline sulfonamides can be prepared as shown below.
  • compounds of type 3.2 can be prepared according to reaction Scheme 3B above.
  • compounds of type 3.2 can be prepared by reduction of an appropriate ester, e.g., 3.1 as shown above. The reduction is carried out in the presence of an appropriate base, e.g., lithium hydroxide, in an appropriate solvent system, e.g., tetrahydrofuran and water, for an appropriate period of time, e.g., 3 hours.
  • an appropriate base e.g., lithium hydroxide
  • solvent system e.g., tetrahydrofuran and water
  • the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactants above (compounds similar to compound of type 3.3 ), can be substituted in the reaction to provide substituted quinazoline sulfonamides similar to Formula 3.4.
  • substituted quinazoline sulfonamides can be prepared as shown below.
  • compounds of type 4.3 can be prepared according to reaction Scheme 4B above.
  • compounds of type 4.2 can be prepared by a substitution reaction of an appropriate hydroxyl, e.g., 4.3 as shown above.
  • Appropriate hydroxyls are commercially available or prepared by methods known to one skilled in the art.
  • the substitution reaction is carried out in the presence of an appropriate halide source, e.g., phosphoryl chloride, at an appropriate temperature, e.g., 110 °C, for an appropriate period of time, e.g., 16 hours.
  • an appropriate halide source e.g., phosphoryl chloride
  • Compounds of type 4.3 can be prepared by a coupling reaction of an appropriate quinazoline derivative, e.g., 4.2 as shown above, and an appropriate amine, e.g., 1.4 as shown above.
  • the coupling reaction is carried out in the presence of an appropriate base, e.g., triethylamine, in an appropriate solvent, e.g., N-methyl-2-pyrrolidone, at an appropriate temperature, e.g., 140 °C, for an appropriate period of time, e.g., 30 minutes.
  • the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactants above (compounds similar to compounds of type 1.10, 4.4, and 4.5 ), can be substituted in the reaction to provide substituted quinazoline sulfonamides similar to Formula 4.6.
  • substituted quinazoline sulfonamides can be prepared as shown below.
  • compounds of type 5.3-5.8, and similar compounds can be prepared according to reaction Scheme 5B above.
  • compounds of type 5.3 can be prepared by a carbonylation reaction of an appropriate aryl bromide, e.g., 5.2 as shown above, and an appropriate amine, e.g., silazane.
  • Appropriate amines are commercially available or prepared by methods known to one skilled in the art.
  • the carbonylation reaction is carried out in the presence of an appropriate catalyst, e.g., palladium (II) acetate, an appropriate ligand, e.g., 1,3-bis(diphenylphosphino)propane, and an appropriate base, e.g., N,N-diisopropylethylamine, at an appropriate temperature, e.g., 100 °C, for an appropriate period of time, e.g., 4 hours.
  • an appropriate catalyst e.g., palladium (II) acetate
  • an appropriate ligand e.g., 1,3-bis(diphenylphosphino)propane
  • an appropriate base e.g., N,N-diisopropylethylamine
  • Compounds of type 5.4 can be prepared by a cyanation reaction of an appropriate aryl bromide, e.g., 5.2 as shown above.
  • the cyanation reaction is carried out in the presence of an appropriate metal cyanide, e.g., zinc cyanide, and an appropriate catalyst, e.g., tetrakis(triphenylphosphine)palladium (0), in an appropriate solvent, e.g., N-methyl-2-pyrrolidone, at an appropriate temperature, e.g., 130 °C, for an appropriate period of time, e.g., 30 minutes.
  • Compounds of type 5.5 can be prepared by a coupling reaction of an appropriate aryl bromide, e.g., 5.2 as shown above, and an appropriate amine, e.g., morpholine as shown above.
  • amines are commercially available or prepared by methods known to one skilled in the art.
  • the coupling reaction is carried out in the presence of an appropriate base, e.g., sodium tert-butoxide, an appropriate catalyst, e.g., tris(dibenzylideneacetone)dipalladium (0), and an appropriate ligand, e.g., 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP), in an appropriate solvent, e.g., 1,4-dioxane, at an appropriate temperature, e.g., 110 °C, for an appropriate period of time, e.g., 1 hour.
  • an appropriate base e.g., sodium tert-butoxide
  • an appropriate catalyst e.g., tris(dibenzylideneacetone)dipalladium (0)
  • an appropriate ligand e.g., 2,2'-bis(diphenylphosphin
  • Compounds of type 5.6 can be prepared by a coupling reaction of an appropriate aryl bromide, e.g., 5.2 as shown above, and an appropriate organotin reagent, e.g., 2-(tributylstannyl)oxazole as shown above.
  • organotin reagents are commercially available or prepared by methods known to one skilled in the art.
  • the coupling reaction is carried out in the presence of an appropriate catalyst, e.g., tris(dibenzylideneacetone)dipalladium (0), in an appropriate solvent, e.g., 1,4-dioxane, at an appropriate temperature, e.g., 110 °C, for an appropriate period of time, e.g., 30 minutes.
  • an appropriate catalyst e.g., tris(dibenzylideneacetone)dipalladium (0)
  • an appropriate solvent e.g., 1,4-dioxane
  • Compounds of type 5.7 can be prepared by a coupling reaction of an appropriate aryl bromide, e.g., 5.2 as shown above, and an appropriate organoborane, e.g., trimethyl boroxime as shown above.
  • Appropriate organoboranes are commercially available or prepared by methods known to one skilled in the art.
  • the coupling reaction is carried out in the presence of an appropriate catalyst, e.g., tetrakis(triphenylphosphine)palladium (0), and an appropriate base, e.g., potassium carbonate, in an appropriate solvent, e.g., 1,4-dioxane, at an appropriate temperature, e.g., 120 °C, for an appropriate period of time, e.g., 1 hour.
  • an appropriate catalyst e.g., tetrakis(triphenylphosphine)palladium (0)
  • an appropriate base e.g., potassium carbonate
  • an appropriate solvent e.g., 1,4-dioxane
  • Compounds of type 5.8 can be prepared by a coupling reaction of an appropriate aryl bromide, e.g., 5.2, and an appropriate amide, e.g., pivalamide as shown above.
  • Appropriate amides are commercially available or prepared by one skilled in the art
  • the coupling reaction is carried out in the presence of an appropriate catalyst, e.g., copper (I) iodide, an appropriate ligand, e.g., N,N'-dimethylethylenediamine, and an appropriate salt, e.g., tripotassium phosphate, in an appropriate solvent, e.g., 1.4-dioxane, at an appropriate temperature, e.g., 100 °C, for an appropriate period of time, e.g., 16 hours.
  • an appropriate catalyst e.g., copper (I) iodide
  • an appropriate ligand e.g., N,N'-dimethylethylenediamine
  • an appropriate salt e.g., tripotassium phosphate
  • the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactants above (compounds similar to compounds of type 5.2 ), can be substituted in the reaction to provide substituted quinazoline sulfonamides similar to Formulas 5.3, 5.4, 5.5, 5.6, 5.7, and 5.8.
  • substituted quinazoline sulfonamides can be prepared as shown below.
  • compounds of type 6.7 can be prepared according to reaction Scheme 6B above.
  • compounds of type 6.2 can be prepared by electrophilic aromatic substitution of an appropriate arene, e.g., 6.1 as shown above.
  • Appropriate arenes are commercially available or prepared by methods known to one skilled in the art.
  • the electrophilic aromatic substitution is carried out in the presence of an appropriate electrophile, e.g., iodine monochloride, and an appropriate base, e.g., methanol, in an appropriate solvent, e.g., dichloromethane, for an appropriate period of time, e.g., 1 hour.
  • Compounds of type 6.3 can be prepared by a cyanation reaction of an appropriate aryl iodide, e.g., 6.2 as shown above.
  • the cyanation reaction is carried out in the presence of an appropriate metal cyanide, e.g., zinc cyanide, in an appropriate solvent, e.g., N-methyl-2-pyrrolidone, at an appropriate temperature, e.g., 150 °C, for an appropriate period of time, e.g., 2 hours.
  • Compounds of type 6.4 can be prepared by hydrolysis of an appropriate aryl cyanide, e.g., 6.3 as shown above.
  • the hydrolysis is carried out in the presence of an appropriate base, e.g., 6N sodium hydroxide, in an appropriate solvent, e.g., 1,4-dioxane, at an appropriate temperature, e.g., 100 °C, for an appropriate period of time, e.g., 16 hours.
  • an appropriate base e.g., 6N sodium hydroxide
  • an appropriate solvent e.g., 1,4-dioxane
  • Compounds of type 6.5 can be prepared by cyclization of an appropriate aryl carboxylic acid, e.g., 6.4 as shown above, and an appropriate amidine, e.g., formamidine acetate as shown above.
  • Appropriate amidines are commercially available or prepared by methods known to one skilled in the art.
  • the cyclization is carried out in the presence of an appropriate solvent, e.g., ethoxy ethanol, at an appropriate temperature, e.g., 130 °C, for an appropriate period of time, e.g., 24 hours.
  • an appropriate solvent e.g., ethoxy ethanol
  • Compounds of type 6.6 can be prepared by a substitution reaction of an appropriate aryl alcohol, e.g., 6.5 as shown above, and an appropriate electrophile, e.g., oxalyl dichloride as shown above.
  • the substitution reaction is carried out in the presence of an appropriate base, e.g., triethylamine, and an appropriate solvent system, e.g., dimethylformamide (DMF) and dichloromethane, for an appropriate period of time, e.g., 16 hours.
  • DMF dimethylformamide
  • Compounds of type 6.7 can be prepared by a coupling reaction of an appropriate aryl halide, e.g., 6.6 as shown above, and an appropriate amine, e.g., 1.4 as shown above.
  • the coupling reaction is carried out in the presence of an appropriate base, e.g., N,N-diisopropylethylamine, in an appropriate solvent, e.g., N-methyl-2-pyrrolidinone, for an appropriate period of time, e.g., 4 hours.
  • the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactants above (compounds similar to compounds of type 1.10, 6.8, 6.9, 6.10, 6.11, 6.12, and 6.13 ), can be substituted in the reaction to provide substituted quinazoline sulfonamides similar to Formula 6.14.
  • substituted quinazoline sulfonamides can be prepared as shown below.
  • compounds of type 7.4, and similar compounds can be prepared according to reaction Scheme 7B above.
  • compounds of type 7.3 can be prepared by an alkylation reaction of an appropriate amine, e.g., 7.1 as shown above, and an appropriate alkyl halide, e.g., 7.2 as shown above.
  • Appropriate alkyl halides are commercially available or prepared by methods known to one skilled in the art.
  • the alkylation reaction is carried out in the presence of an appropriate base, e.g., potassium carbonate, in an appropriate solvent, e.g., 1,4-dioxane, at an appropriate temperature, e.g., 80 °C, for an appropriate period of time, e.g., 6 hours.
  • Compounds of type 7.4 can be prepared by hydrogenation of an appropriate aryl halide, e.g., 7.3 as shown above.
  • the hydrogenation is carried out in the presence of an appropriate hydrogen source, e.g., hydrogen gas, and an appropriate catalyst, e.g., palladium on carbon, in an appropriate solvent, e.g., ethyl acetate, for an appropriate period of time, e.g., 4 hours.
  • an appropriate hydrogen source e.g., hydrogen gas
  • an appropriate catalyst e.g., palladium on carbon
  • the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactants above (compounds similar to compounds of type 7.5, 7.6, and 7.7 ), can be substituted in the reaction to provide substituted quinazoline sulfonamides similar to Formula 7.8.
  • substituted quinazoline sulfonamides can be prepared as shown below.
  • compounds of type 8.4 can be prepared according to reaction Scheme 8B above.
  • compounds of type 8.2 can be prepared by deprotection of an appropriate amine, e.g., 8.1 as shown above. The deprotection is carried out in the presence of an appropriate deprotecting agent, e.g., hydrochloric acid, in an appropriate solvent system, e.g., 1,4-dioxane and dichloromethane, for an appropriate period of time, e.g., 2 hours.
  • an appropriate deprotecting agent e.g., hydrochloric acid
  • Compounds of type 8.4 can be prepared by a sulfonylation reaction of an appropriate amine, e.g., 8.2 as shown above, and an appropriate sulfonyl halide, e.g., 8.3 as shown above.
  • the sulfonylation reaction is carried out in the presence of an appropriate base, e.g., triethylamine, in an appropriate solvent, e.g., dichloromethane, for an appropriate period of time, e.g., 30 minutes.
  • the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactants above (compounds similar to compounds of type 8.1, 8.2, and 8.3 ), can be substituted in the reaction to provide substituted quinazoline sulfonamides similar to Formula 8.4.
  • substituted quinazoline sulfonamides can be prepared as shown below.
  • compounds of type 9.7, and similar compounds can be prepared according to reaction Scheme 9B above.
  • compounds of type 9.2 can be prepared by epoxidation of an appropriate ketone, e.g., 9.1 as shown above.
  • Appropriate ketones are commercially available or prepared by methods known to one skilled in the art.
  • the epoxidation is carried out in the presence of an appropriate sulfoxonium agent, e.g., trimethylsulfoxonium iodide, and an appropriate base, e.g., 60% sodium hydride, in an appropriate solvent, e.g., dimethylsulfoxide (DMSO), for an appropriate period of time, e.g., 12 hours.
  • an appropriate sulfoxonium agent e.g., trimethylsulfoxonium iodide
  • an appropriate base e.g., 60% sodium hydride
  • an appropriate solvent e.g., dimethylsulfoxide (DMSO)
  • Compounds of type 9.4 can be prepared by a nucleophilic substitution reaction of an appropriate epoxide, e.g., 9.2 as shown above, and an appropriate nucleophile, e.g., 9.3 as shown above.
  • the nucleophilic substitution reaction is carried out in the presence of an appropriate base, e.g., benzyl triethylammonium chloride (TEBAC), in an appropriate solvent, e.g., dioxane, at an appropriate temperature, e.g., 90 °C, for an appropriate period of time, e.g., 16 hours.
  • Compounds of type 9.5 can be prepared by deprotection of an appropriate amine, e.g., 9.4 as shown above.
  • the deprotection is carried out in the presence of an appropriate deprotecting agent, e.g., trifluoroacetic acid (TFA), in an appropriate solvent, e.g., dichloromethane, for an appropriate period of time, e.g., 1 hour.
  • an appropriate deprotecting agent e.g., trifluoroacetic acid (TFA)
  • THF trifluoroacetic acid
  • an appropriate solvent e.g., dichloromethane
  • Compounds of type 9.7 can be prepared by a coupling reaction of an appropriate aryl halide, e.g., 9.6 as shown above, and an appropriate amine, e.g., 9.5 as shown above.
  • the coupling reaction is carried out in the presence of an appropriate base, e.g., N,N-diisopropylethylamine, in an appropriate solvent, e.g., dichloromethane, for an appropriate period of time, e.g., 1 hour.
  • an appropriate base e.g., N,N-diisopropylethylamine
  • an appropriate solvent e.g., dichloromethane
  • the method of use is directed to the treatment of a disorder.
  • the disclosed compounds can be used as single agents or in combination with one or more other drugs in the treatment, prevention, control, amelioration, or reduction of risk of the aforementioned diseases, disorders and conditions for which the compound or the other drugs have utility, where the combination of drugs together are safer or more effective than either drug alone.
  • the other drug(s) can be administered by a route and in an amount commonly used therefore, contemporaneously or sequentially with a disclosed compound.
  • a pharmaceutical composition in unit dosage form containing such drugs and the disclosed compound is preferred.
  • the combination therapy can also be administered on overlapping schedules. It is also envisioned that the combination of one or more active ingredients and a disclosed compound can be more efficacious than either as a single agent.
  • compositions and methods of the present invention can further comprise other therapeutically active compounds as noted herein which are usually applied in the treatment of the above mentioned pathological conditions.
  • the invention relates to a method for the manufacture of a medicament for treating or preventing a disorder associated with elevated TXNIP and/or glucagon in a mammal, the method comprising combining a therapeutically effective amount of a disclosed compound or product of a disclosed method with a pharmaceutically acceptable carrier or diluent.
  • the disorder associated with elevated TXNIP and/or glucagon is a disorder affecting regulation of hepatic glucose production.
  • the disorder associated with elevated TXNIP is diabetes.
  • the diabetes is selected from Type I diabetes, Type II diabetes, and gestational diabetes.
  • the diabetes is Type I diabetes.
  • the diabetes is Type II diabetes.
  • the diabetes is gestational diabetes.
  • the present method includes the administration to an animal, particularly a mammal, and more particularly a human, of a therapeutically effective amount of the compound effective in the inhibition of TXNIP expression and TXNIP protein signaling.
  • the dose administered to an animal, particularly a human, in the context of the present invention should be sufficient to affect a therapeutic response in the animal over a reasonable time frame.
  • dosage will depend upon a variety of factors including the condition of the animal, the body weight of the animal, as well as the severity and stage of the disorder.
  • the invention relates to the manufacture of a medicament comprising combining a disclosed compound or a product of a disclosed method of making, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, with a pharmaceutically acceptable carrier or diluent.
  • the invention relates to the uses for inhibition of TXNIP expression or function and/or reduction of glucagon levels.
  • the use is treatment of a disorder associated with elevated TXNIP and/or glucagon (e.g., diabetes or diabetes related disorders).
  • the invention relates to the use of a disclosed compound or product of a disclosed method in the manufacture of a medicament for the treatment of a disorder associated with TXNIP activity such as, for example, a disorder associated with elevated TXNIP (e.g., diabetes or diabetes related disorders).
  • a disorder associated with TXNIP activity such as, for example, a disorder associated with elevated TXNIP (e.g., diabetes or diabetes related disorders).
  • the disorder associated with elevated TXNIP and/or glucagon is a disorder affecting the regulation of hepatic glucose production.
  • the disorder associated with elevated TXNIP is diabetes.
  • the diabetes is selected from Type I diabetes, Type II diabetes, and gestational diabetes.
  • the diabetes is Type I diabetes.
  • the diabetes is Type II diabetes.
  • the disorder is gestational diabetes.
  • hyperlipidemia and/or fatty liver disease e.g., nonalcoholic fatty liver disease
  • the hyperlipidemia and/or fatty liver disease is optionally associated with elevated TXNIP and/or glucagon, but is not necessarily so associated.
  • the hyperlipidemia and/or fatty liver disease is optionally related with diabetes, but is not necessarily related to diabetes.
  • the use relates to a process for preparing a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a disclosed compound or a product of a disclosed method, and a pharmaceutically acceptable carrier, for use as a medicament.
  • the use relates to a process for preparing a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a disclosed compound or a product of a disclosed method, wherein a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of the disclosed compound or the product of a disclosed method.
  • the use relates to the treatment of a disorder in a vertebrate animal. In a further aspect, the use relates to the treatment of a disorder in a human subject.
  • the disclosed uses can be employed in connection with the disclosed compounds, methods, compositions, and kits.
  • the invention relates to the use of a disclosed compound or composition of a medicament for the treatment of a disorder associated with elevated TXNIP and/or glucagon and or for treatment of hyperlipidemia and/or fatty liver disease in a mammal.
  • kits comprising an effective amount of a compound having a structure represented by a formula: and wherein n is 0, 1, or 2; wherein p is 0, 1, 2, 3, or 4; wherein q is 0 or 1; wherein R 1 is -NH 2 , - OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, -(C1-C4 alkyl)(C1-C4 alkoxy), -(C1-C4 alkyl)COzH, or Cy 1 ; wherein Cy 1 , when present, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -NH 2 , -OH, C
  • kits comprising an effective amount of a compound having a structure represented by a formula: wherein n is 0, 1, or 2; wherein each of p and q is independently 0 or 1; wherein R 1 is -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, or Cy 1 ; wherein Cy 1 , when present, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -NH 2 , -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamin
  • the agents and pharmaceutical compositions described herein can be provided in a kit.
  • the kit can also include combinations of the agents and pharmaceutical compositions described herein.
  • the informational material can be descriptive, instructional, marketing or other material that relates to the methods described herein and/or to the use of the agents for the methods described herein.
  • the informational material may relate to the use of the agents herein to treat a subject who has, or who is at risk for developing, a disorder associated with elevated TXNIP.
  • the kits can also include paraphernalia for administering the agents of this invention to a cell (in culture or in vivo ) and/or for administering a cell to a patient.
  • the informational material can include instructions for administering the pharmaceutical composition and/or cell(s) in a suitable manner to treat a human, e.g., in a suitable dose, dosage form, or mode of administration (e.g., a dose, dosage form, or mode of administration described herein).
  • the informational material can include instructions to administer the pharmaceutical composition to a suitable subject, e.g ., a human having, or at risk for developing, a disorder associated with elevated TXNIP.
  • the composition of the kit can include other ingredients, such as a solvent or buffer, a stabilizer, a preservative, a fragrance or other cosmetic ingredient.
  • the kit can include instructions for admixing the agent and the other ingredients, or for using one or more compounds together with the other ingredients.
  • the compound and the at least one agent known are co-formulated. In a still further aspect, the compound and the at least one agent are co-packaged.
  • the kit further comprises a plurality of dosage forms, the plurality comprising one or more doses; wherein each dose comprises an effective amount of the compound and the at least one agent.
  • the effective amount is a therapeutically effective amount.
  • the effective amount is a prophylactically effective amount.
  • each dose of the compound and the at least one agent are co-packaged.
  • each dose of the compound and the at least one agent are co-formulated.
  • the subject of the herein disclosed methods is a vertebrate, e.g., a mammal.
  • the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent.
  • the term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered.
  • a patient refers to a subject afflicted with a disease or disorder.
  • patient includes human and veterinary subjects.
  • the subject has been diagnosed with a need for treatment prior to the administering step. In some aspects of the disclosed method, the subject has been diagnosed with a disorder associated with elevated TXNIP prior to the administering step. In some aspects of the disclosed methods, the subject has been identified with a need for treatment prior to the administering step. In one aspect, a subject can be treated prophylactically with a compound or composition disclosed herein, as discussed herein elsewhere.
  • Toxicity and therapeutic efficacy of the agents and pharmaceutical compositions described herein can be determined by standard pharmaceutical procedures, using either cells in culture or experimental animals to determine the LD 50 (the dose lethal to 50% of the population) and the ED 50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the ratio LD 50 /ED 50 .
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED 50 with little or no toxicity, and with little or no adverse effect on a human's ability to hear.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • the therapeutically effective dose can be estimated initially from cell culture assays.
  • a dose can be formulated in animal models to achieve a circulating plasma concentration range that includes the IC 50 (that is, the concentration of the test compound which achieves a half-maximal inhibition of symptoms) as determined in cell culture. Such information can be used to more accurately determine useful doses in humans.
  • Exemplary dosage amounts of a differentiation agent are at least from about 0.01 to 3000 mg per day, e.g., at least about 0.00001, 0.0001, 0.001, 0.01, 0.1, 1, 2, 5, 10, 25, 50, 100, 200, 500, 1000, 2000, or 3000 mg per kg per day, or more.
  • the formulations and routes of administration can be tailored to the disease or disorder being treated, and for the specific human being treated.
  • a subject can receive a dose of the agent once or twice or more daily for one week, one month, six months, one year, or more.
  • the treatment can continue indefinitely, such as throughout the lifetime of the human.
  • Treatment can be administered at regular or irregular intervals (once every other day or twice per week), and the dosage and timing of the administration can be adjusted throughout the course of the treatment.
  • the dosage can remain constant over the course of the treatment regimen, or it can be decreased or increased over the course of the treatment.
  • the dosage facilitates an intended purpose for both prophylaxis and treatment without undesirable side effects, such as toxicity, irritation or allergic response.
  • undesirable side effects such as toxicity, irritation or allergic response.
  • human doses can readily be extrapolated from animal studies ( Katocs et al., (1990) Chapter 27 in Remington's Pharmaceutical Sciences, 18th Ed., Gennaro, ed., Mack Publishing Co., Easton, PA ).
  • the dosage required to provide an effective amount of a formulation will vary depending on several factors, including the age, health, physical condition, weight, type and extent of the disease or disorder of the recipient, frequency of treatment, the nature of concurrent therapy, if required, and the nature and scope of the desired effect(s) ( Nies et al., (1996) Chapter 3, In: Goodman & Gilman's The Pharmacological Basis of Therapeutics, 9th Ed., Hardman et al., eds., McGraw-Hill, New York, NY ).
  • routes of administering the disclosed compounds and compositions can be administered by direct therapy using systemic administration and/or local administration.
  • the route of administration can be determined by a patient's health care provider or clinician, for example following an evaluation of the patient.
  • an individual patient's therapy may be customized, e.g ., the type of agent used, the routes of administration, and the frequency of administration can be personalized.
  • therapy may be performed using a standard course of treatment, e.g ., using pre-selected agents and pre-selected routes of administration and frequency of administration.
  • Systemic routes of administration can include, but are not limited to, parenteral routes of administration, e.g ., intravenous injection, intramuscular injection, and intraperitoneal injection; enteral routes of administration e.g ., administration by the oral route, lozenges, compressed tablets, pills, tablets, capsules, drops ( e.g ., ear drops), syrups, suspensions and emulsions; rectal administration, e.g ., a rectal suppository or enema; a vaginal suppository; a urethral suppository; transdermal routes of administration; and inhalation ( e.g ., nasal sprays).
  • parenteral routes of administration e.g ., intravenous injection, intramuscular injection, and intraperitoneal injection
  • enteral routes of administration e.g ., administration by the oral route, lozenges, compressed tablets, pills, tablets, capsules, drops ( e.g ., ear drops), syrups, suspensions
  • the Rat INS-1 cell line was obtained from UAB and maintained in RPMI-1640 (Invitrogen #11875) supplemented with 10% fetal bovine serum (FBS), 100 U/ml penicillin and 100 mg/ml streptomycin, 10 mM HEPES, 1 mM Sodium Pyruvate, 50 ⁇ M 2-Mercaptoethanol, and 11.1 mM Glucose in a humidified incubator with a 5% COz atmosphere at 37 °C. 4 ⁇ 10 4 cells per well were seeded to 96-well plate and incubated at 37 °C overnight. A subset of the cells were then cultured in medium with 5 mM Glucose for 24 hrs and then treated in medium with 25 mM glucose with or without compounds to be tested for another 24 hrs.
  • FBS fetal bovine serum
  • HEPES 1 mM Sodium Pyruvate
  • 50 ⁇ M 2-Mercaptoethanol 50 ⁇ M 2-Mercaptoethanol
  • the cell composition is calculated and cells are diluted to 4 ⁇ 10 5 cells/ml. 100 ⁇ l are then added to each well and diluted to 4 ⁇ 10 4 cells/well.
  • the human TXNIP promoter region including -1518 bp upstream of the ATG start codon was subcloned into the pGL4.17 [luc2/Neo] vector (Promega) to generate the luciferase reporter plasmid and was verified by sequencing.
  • INS-1 cells were transfected with this pGL4.17-human TXNIP promoter luciferase plasmid (0.4 ⁇ g/well) using DharmaFECT Duo transfection reagent (1 ⁇ l/well; Dharmacon). 48 h after transfection, Geneticin (100 ⁇ g/ml, Invitrogen) was added to select stable transfected cells. After all Geneticin-sensitive cells of the control wells (no transfection) had died, single clones were picked and the dose of Geneticin was reduced to the maintenance dose of 50 ⁇ g/ml, which was used thereafter for expansion and culture of these cells.
  • Cells were maintained in medium containing 500 ml RPMI 1640 with 11.1 mM of glucose (Invitrogen, # 11875), 50 ml FBS (Invitrogen, # 16140), 5 ml Pen/Strep (Invitrogen, # 15140), 5.5 ml 1M HEPES solution (Invitrogen, #15630), 5.5 ml 100X Sodium Pyruvate (Invitrogen, #11360), and 150 mg L-glutamine (Sigma, #G3126-100G) and for each 10 ml of medium, 35 ⁇ l of 1:1000 diluted ⁇ -Mercaptoethanol (Fisher, # ICN19470583) as well as 10 ⁇ l of Geneticin (Invitrogen, #10131) were freshly added each time.
  • a Dual-Luciferase ® Reporter Assay System (Promega, CAT#E1960) was used according to commercial instructions. Briefly, 24 h after the transfection growth media was removed from the cultured cells. Cells were then rinsed with 200 ⁇ l PBS. After decanting the PBS, the cells were incubated in 25 ⁇ l of PLB with gentle rocking for 15 min at RT. Then 20 ⁇ l of cell lysate in PLB were transferred to Eppendorf tubes containing 100 ⁇ l of LAR (i.e., Luciferase Assay Substrate in Luciferase Assay Buffer).
  • LAR i.e., Luciferase Assay Substrate in Luciferase Assay Buffer
  • HTS high throughput screening
  • the SYBR Green assay was performed using a LightCycler 480 II (Roche Applied Science) with an initial incubation at 50 °C for 10 min for RT followed by denaturation at 95 °C for 5 min. Forty cycles of amplification were performed using a thermal cycling profile of 95 °C for 10s, 60 °C for 30 s. Subsequently, a melting curve was recorded by holding at 95 °C for 60 s, cooling to 60 °C for 60 s, and then heating at 0.11 °C/s up to 95 °C. The data was collected and analyzed using the LightCycler 480 Software Release 1.5.0 SP3.
  • TXNIP mRNA The relative amount of TXNIP mRNA was normalized to 18 s rRNA level as a housekeeping gene, and the data was analyzed according to the 2 - ⁇ C T method (1). The transformed data was expressed as % inhibition and compound IC50 calculated by a 4-parameter logistic fit of the data using GraphPad Prism 7.
  • TXNIP inhibitory effect of lead compounds and derivatives was further confirmed manually using dual-luciferase assays including a control renilla luciferase plasmid, quantitative real-time RT-PCR and Western blotting with the anti-TXNIP IgG (JY2; # K0205-3; 1:1000; MBL, Woburn, MA), to assure compound-induced TXNIP inhibition also at the protein level.
  • INS-1 cell viability was determined based on quantification of ATP using Cell Titer-Glo Luminescent Cell Viability Assay kit (Promega #G7572), which indicates the presence of metabolically active cells. Briefly, INS-1 cells were seeded into 96-well plates at a cell density of 4.5 ⁇ 10 4 and 3.5 ⁇ 10 4 cells per well and incubated overnight at 37 °C with 5% CO2. On the following day, cells were treated with compounds for 24 hrs and 72 hrs respectively. Cell Titer-Glo reagent was added to the cells and Luminescence was acquired on Synergy 4 Reader (PerkinElmer).
  • Isolated primary human islets were cultured in the presence or absence of compound #11 (Table 1). The compound specifically inhibited glucose-induced TXNIP expression, as shown in Fig. 1 . Compound #11 also protected human islets against Type 1 diabetes associated pro-inflammatory cytokine-induced TXNIP expression and ⁇ -cell apoptosis, as shown in Fig. 2 .
  • Compound #11a was administered for three weeks in the drinking water of wild-type mice at about 100mg/kg/d.
  • the treated mice showed no change in body weight as compared to untreated controls and no gross abnormalities in organs upon sacrifice. However, the treated mice showed a small but significant decrease in blood glucose levels. Fasting serum glucagon levels were decreased in treated mice as compared to control mice, suggesting compound #11a affected alpha cell glucagon secretion. Indeed, incubation of alpha TC1-6 cells with compound #11a resulted in decreased glucagon secretion.
  • Oral administration of compound #11a to wild-type mice resulted in significantly lower levels of non-esterified fatty acids and of triglycerides in the serum as compared to control mice not receiving compound treatment.
  • liver triglyceride levels in compound-treated mice were two-fold lower than in control mice.
  • mice Oral administration of compound #11a (100mg/kg/d) to mice starting after completion of the multiple low-dose STZ regimen, effectively protected against diabetes ( Fig. 3 ).
  • the mice maintained a normal body weight and no detrimental effects or abnormalities were noticed in response to compound treatment throughout the experiment or upon sacrifice and dissection.
  • Obese, insulin-resistant and diabetic, leptin receptor-deficient db/db mice were administered compound #11a as described above for 4 weeks. Similar to the STZ-treated mice, the db/db mice showed no difference in body weight as compared to untreated db/db mice. However, blood glucose levels in the treated animals decreased significantly within days of starting treatment with compound #11a and remained within the normal range for the remainder of the study ( Fig. 3 ). The treated mice showed a significant decrease in fasting serum glucagon levels similar to the decrease observed in lean wild-type mice.
  • substituted quinazoline sulfonamides possess good pharmacokinetic properties and are capable of effectively inhibiting TXNIP expression, lowering glucagon levels and hepatic glucose production and of treating and preventing diabetes. In addition, they can lower liver and serum lipid levels
  • mice After having been rendered overtly diabetic by multiple low-dose STZ injections, mice received compound #11a by gavage at a dose of 100mg/kg b.i.d or 30mg/kg b.i.d. or received a vehicle control. Blood glucose levels significantly decreased in a dose-dependent manner in the mice receiving compound #11a, whereas hyperglycemia continued to worsen in vehicle treated mice.
  • reaction mixture Upon complete consumption of the starting material, the reaction mixture was poured into water (20 mL), extracted with EtOAc (2 ⁇ 20 mL). The organic extracts were washed with water (2 ⁇ 20 mL), brine (20 mL), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (gradient elution 70-80% of EtOAc in hexanes) to afford 1.10 (190 mg, 59 %) as a yellow solid.
  • reaction mixture was poured into water (25 mL), extracted with EtOAc (2 ⁇ 25 mL). The organic extracts were washed with saturated NaHCO 3 (25 mL), water (25 mL), brine (25 mL), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (gradient elution 90-100% of EtOAc in hexanes) to afford 22 (62 mg, 37 %) as yellow solid.
  • reaction mixture was filtered through celite pad, washed with EtOAc (50 mL) and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (gradient elution 2-5 % of MeOH in CH 2 Cl 2 ) to afford 24 (18 mg, 18%) as a yellow solid.
  • reaction mixture was filtered through pad of celite, washed with EtOAc (50 mL) and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting (MeOH: CH 2 Cl 2 ; 0.3: 9.7). Fractions containing the product were combined and concentrated under reduced pressure to afford 26 (55 mg, 36 %) as a white solid.
  • reaction mixture was filtered through celite pad, washed with EtOAc (50 mL) and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting (MeOH: CH 2 Cl 2 ; 0.5: 9.5). Fractions containing the product were combined and concentrated under reduced pressure to afford 27 (62 mg, 31 %) as a pink solid.

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Claims (20)

  1. Verbindung umfassend eine Struktur, die durch eine Formel dargestellt ist, die ausgewählt ist aus:
    Figure imgb0390
     und
    Figure imgb0391
    wobei n 0, 1, oder 2 ist;
    wobei p 0, 1, 2, 3, oder 4 ist;
    wobei q 0 oder 1 ist;
    wobei R1-NH2, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Hydroxyalkyl, C1-C4-Alkylamino, (C1-C4)(C1-C4)-Dialkylamino, -(C1-C4-Alkyl)(C1-C4-Alkoxy), -(C1-C4-Alkyl)CO2H, oder Cy1 ist;
    wobei Cy1, wenn vorhanden, C3-C6-Cycloalkyl, C2-C5-Heterocycloalkyl, oder Aryl ist, und mit 0, 1, 2 oder 3 Gruppen substituiert ist, die unabhängig ausgewählt sind aus Halogen, -NH2, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, und (C1-C4)(C1-C4)-Dialkylamino;
    wobei R2 Wasserstoff oder C1-C4-Alkyl ist, oder wobei jedes von R1 und R2 kovalent miteinander verbunden ist und zusammen mit den Zwischenatomen ein 3- bis 6-gliedriges Heterocycloalkyl aufweist, das mit 0, 1, 2 oder 3 Gruppen substituiert ist, die unabhängig ausgewählt sind aus Halogen, -NH2, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, und (C1-C4)(C1-C4)-Dialkylamino;
    wobei R3 Wasserstoff oder C1-C4-Alkyl ist, oder wobei jedes von R1 und R3 kovalent miteinander verbunden sind und zusammen mit den Zwischenatomen ein 5- bis 7-gliedriges Heterocycloalkyl aufweisen, das mit 0, 1, 2 oder 3 Gruppen substituiert ist, die unabhängig ausgewählt sind aus Halogen, -NH2, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, und (C1-C4)(C1-C4)-Dialkylamino;
    wobei R4 Wasserstoff, Halogen, -NH2, -OH, C1-C4-Alkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, (C1-C4)(C1-C4)-Dialkylamino, oder Cy2 ist;
    wobei Cy2, wenn vorhanden, C3-C6-Cycloalkyl, C2-C5-Heterocycloalkyl, oder Aryl ist, und mit 0, 1, 2 oder 3 Gruppen substituiert ist, die unabhängig ausgewählt sind aus Halogen, -NH2, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, und (C1-C4)(C1-C4)-Dialkylamino;
    wobei jedes von R5a, R5b, R5c, und R5d unabhängig Wasserstoff, Halogen, -NH2, -CN, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Haloalkoxy, C1-C4-Alkylamino, (C1-C4)(C1-C4)-Dialkylamino, -CO2(C1-C4-Alkyl), -CO2H, -CO2NH2, -NHC(O)Cy3, -NHC(O)(C1-C4-Alkyl), oder Cy3 ist;
    wobei Cy3, wenn vorhanden, C3-C6-Cycloalkyl, C2-C5-Heterocycloalkyl, oder Aryl ist, und mit 0, 1, 2 oder 3 Gruppen substituiert ist, die unabhängig ausgewählt sind aus Halogen, -NH2, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, und (C1-C4)(C1-C4)-Dialkylamino;
    wobei A O, NR6a, oder CHR6b ist;
    wobei R6a Wasserstoff oder C1-C4-Alkyl ist; und
    wobei R6b Wasserstoff, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, (C1-C4)(C1-C4)-Dialkylamino, oder-CO2H ist;
    wobei R7 Wasserstoff, Halogen, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, oder C1-C4-Alkoxy ist;
    wobei jedes Auftreten von R8a und R8b, wenn vorhanden, unabhängig Wasserstoff, C1-C4-Alkyl, C1-C4-Halogenalkyl, Phenyl, oder-CO2H ist;
    oder wobei p 1 ist und jedes von R8a und R8b zusammen =O aufweist; und
    wobei R9 Wasserstoff, C1-C4-Alkyl, oder Cy4 ist,
    wobei Cy4, wenn vorhanden, C3-C6-Cycloalkyl, C2-C5-Heterocycloalkyl, oder Aryl ist, und mit 0, 1, 2 oder 3 Gruppen substituiert ist, die unabhängig ausgewählt sind aus Halogen, -NH2, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, und (C1-C4)(C1-C4)-Dialkylamino,
    oder ein pharmazeutisch verträgliches Salz davon, zur Verwendung in einem Verfahren zur Behandlung einer Störung, die mit erhöhtem TXNIP oder erhöhtem Glucagon in einem Säuger assoziiert ist, wobei die Behandlung den Schritt zur Verabreichung einer therapeutisch wirksamen Menge der Verbindung an den Säuger aufweist, wobei die Störung, die mit erhöhtem TXNIP oder erhöhtem Glucagon in einem Säuger assoziiert ist, ausgewählt ist aus Diabetes oder einer mit Diabetes in Zusammenhang stehenden Störung, Hyperlipidämie oder Fettlebererkrankung.
  2. Verbindung umfassend eine Struktur, die durch eine Formel dargestellt ist, die ausgewählt ist aus:
    Figure imgb0392
    Figure imgb0393
    wobei n 0, 1, oder 2 ist;
    wobei p 0, 1, 2, 3, oder 4 ist;
    wobei q 0 oder 1 ist;
    wobei R1 -NH2, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Hydroxyalkyl, C1-C4-Alkylamino, (C1-C4)(C1-C4)-Dialkylamino, -(C1-C4-Alkyl)(C1-C4-Alkoxy), -(C1-C4-Alkyl)CO2H, oder Cy1 ist;
    wobei Cy1, wenn vorhanden, C3-C6-Cycloalkyl, C2-C5-Heterocycloalkyl, oder Aryl ist, und mit 0, 1, 2 oder 3 Gruppen substituiert ist, die unabhängig ausgewählt sind aus Halogen, -NH2, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, und (C1-C4)(C1-C4)-Dialkylamino;
    wobei R2 Wasserstoff oder C1-C4-Alkyl ist, oder wobei jedes von R1 und R2 kovalent miteinander verbunden ist und zusammen mit den Zwischenatomen ein 3- bis 6-gliedriges Heterocycloalkyl aufweist, das mit 0, 1, 2 oder 3 Gruppen substituiert ist, die unabhängig ausgewählt sind aus Halogen, -NH2, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, und (C1-C4)(C1-C4)-Dialkylamino;
    wobei R3 Wasserstoff oder C1-C4-Alkyl ist, oder wobei jedes von R1 und R3 kovalent miteinander verbunden ist und zusammen mit den Zwischenatomen ein 5- bis 7-gliedriges Heterocycloalkyl aufweist, das mit 0, 1, 2 oder 3 Gruppen substituiert ist, die unabhängig ausgewählt sind aus Halogen, -NH2, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, und (C1-C4)(C1-C4)-Dialkylamino;
    wobei R4 Wasserstoff, Halogen, -NH2, -OH, C1-C4-Alkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, (C1-C4)(C1-C4)-Dialkylamino, oder Cy2 ist;
    wobei Cy2, wenn vorhanden, C3-C6-Cycloalkyl, C2-C5-Heterocycloalkyl, oder Aryl ist, und mit 0, 1, 2 oder 3 Gruppen substituiert ist, die unabhängig ausgewählt sind aus Halogen, -NH2, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, und (C1-C4)(C1-C4)-Dialkylamino;
    wobei jedes von R5a, R5b, R5c, und R5d unabhängig Wasserstoff, Halogen, -NH2, -CN, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Haloalkoxy, C1-C4-Alkylamino, (C1-C4)(C1-C4)-Dialkylamino, -CO2(C1-C4-Alkyl), -CO2H, -CO2NH2, -NHC(O)Cy3, -NHC(O)(C1-C4-Alkyl), oder Cy3 ist;
    wobei Cy3, wenn vorhanden, C3-C6-Cycloalkyl, C2-C5-Heterocycloalkyl, oder Aryl ist, und mit 0, 1, 2 oder 3 Gruppen substituiert ist, die unabhängig ausgewählt sind aus Halogen, -NH2, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, und (C1-C4)(C1-C4)-Dialkylamino;
    wobei A O, NR6a, oder CHR6b ist;
    wobei R6a Wasserstoff oder C1-C4-Alkyl ist; und
    wobei R6b Wasserstoff, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, (C1-C4)(C1-C4)-Dialkylamino, oder-CO2H ist;
    wobei R7 Wasserstoff, Halogen, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, oder C1-C4-Alkoxy ist;
    wobei jedes Auftreten von R8a und R8b, wenn vorhanden, unabhängig Wasserstoff, C1-C4-Alkyl, C1-C4-Halogenalkyl, Phenyl, oder-CO2H ist;
    oder wobei p 1 ist und jedes von R8a und R8b zusammen =O aufweist; und
    wobei R9 Wasserstoff, C1-C4-Alkyl, oder Cy4 ist,
    wobei Cy4, wenn vorhanden, C3-C6-Cycloalkyl, C2-C5-Heterocycloalkyl, oder Aryl ist, und mit 0, 1, 2 oder 3 Gruppen substituiert ist, die unabhängig ausgewählt sind aus Halogen, -NH2, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, und (C1-C4)(C1-C4)-Dialkylamino,
    oder ein pharmazeutisch verträgliches Salz davon, zur Verwendung nach Anspruch 1 in einem Verfahren zur Behandlung einer Störung, die mit erhöhtem TXNIP oder erhöhtem Glucagon in einem Säuger assoziiert ist, durch Hemmung der TXNIP-Expression oder durch Senkung des Glucagon-Niveaus in einem Säuger, wobei die Behandlung den Schritt zur Verabreichung einer wirksamen Menge der Verbindung an den Säuger aufweist, wobei die Störung, die im Zusammenhang mit erhöhtem TXNIP oder erhöhtem Glucagon in einem Säuger assoziiert ist, ausgewählt ist aus Diabetes oder einer mit Diabetes in Zusammenhang stehenden Störung, Hyperlipidämie oder Fettlebererkrankung.
  3. Verbindung zur Verwendung nach Anspruch 1 oder 2, wobei die Verbindung eine Struktur aufweist, die durch eine Formel dargestellt ist:
    Figure imgb0394
  4. Verbindung zur Verwendung nach Anspruch 3, wobei p 0 oder 1 ist; R1-NH2, - OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, (C1-C4)(C1-C4)-Dialkylamino, oder Cy1 ist; jedes von R5a, R5b, R5c, und R5d unabhängig Wasserstoff, Halogen, -NH2, -CN, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, (C1-C4)(C1-C4)-Dialkylamino, -CO2(C1-C4-Alkyl), -CO2H, -CO2NH2, -NHC(O)Cy3, -NHC(O)(C1-C4-Alkyl), oder Cy3 ist; und R8a Wasserstoff ist und R8b Wasserstoff, C1-C4-Alkyl, oder C1-C4-Halogenalkyl ist.
  5. Verbindung zur Verwendung nach Anspruch 1 oder 2, wobei die Verbindung eine Struktur aufweist, die durch eine Formel dargestellt ist, die ausgewählt ist aus:
    Figure imgb0395
  6. Verbindung zur Verwendung nach Anspruch 1, wobei die Störung Diabetes oder eine mit Diabetes in Zusammenhang stehende Störung ist; oder wobei p 1 ist.
  7. Pharmazeutische Zusammensetzung, umfassend einen pharmazeutisch verträglichen Träger und eine therapeutisch wirksame Menge von mindestens einer Verbindung, die eine durch eine Formel dargestellte Struktur aufweist:
    Figure imgb0396
    wobei n 0, 1, oder 2 ist;
    wobei p 1, 2, 3, oder 4 ist;
    wobei q 0 oder 1 ist;
    wobei R1-NH2, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Hydroxyalkyl, C1-C4-Alkylamino, (C1-C4)(C1-C4)-Dialkylamino, -(C1-C4-Alkyl)(C1-C4-Alkoxy), -(C1-C4-Alkyl)CO2H, oder Cy1 ist;
    wobei Cy1, wenn vorhanden, C3-C6-Cycloalkyl, C2-C5-Heterocycloalkyl, oder Aryl ist, und mit 0, 1, 2 oder 3 Gruppen substituiert ist, die unabhängig ausgewählt sind aus Halogen, -NH2, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, und (C1-C4)(C1-C4)-Dialkylamino;
    wobei R2 Wasserstoff oder C1-C4-Alkyl ist, oder wobei jedes von R1 und R2 kovalent miteinander verbunden ist und zusammen mit den Zwischenatomen ein 3- bis 6-gliedriges Heterocycloalkyl aufweist, das mit 0, 1, 2 oder 3 Gruppen substituiert ist, die unabhängig ausgewählt sind aus Halogen, -NH2, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, und (C1-C4)(C1-C4)-Dialkylamino;
    wobei R3 Wasserstoff oder C1-C4-Alkyl ist, oder wobei jedes von R1 und R3 kovalent miteinander verbunden sind und zusammen mit den Zwischenatomen ein 5- bis 7-gliedriges Heterocycloalkyl aufweisen, das mit 0, 1, 2 oder 3 Gruppen substituiert ist, die unabhängig ausgewählt sind aus Halogen, -NH2, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, und (C1-C4)(C1-C4)-Dialkylamino;
    wobei R4 Wasserstoff, Halogen, -NH2, -OH, C1-C4-Alkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, (C1-C4)(C1-C4)-Dialkylamino, oder Cy2 ist;
    wobei Cy2, wenn vorhanden, C3-C6-Cycloalkyl, C2-C5-Heterocycloalkyl, oder Aryl ist, und mit 0, 1, 2 oder 3 Gruppen substituiert ist, die unabhängig ausgewählt sind aus Halogen, -NH2, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, und (C1-C4)(C1-C4)-Dialkylamino;
    wobei jedes von R5a, R5b, R5c, und R5d unabhängig Wasserstoff, Halogen, -NH2, -CN, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Haloalkoxy, C1-C4-Alkylamino, (C1-C4)(C1-C4)-Dialkylamino, -CO2(C1-C4-Alkyl), -CO2H, -CO2NH2, -NHC(O)Cy3, -NHC(O)(C1-C4-Alkyl), oder Cy3 ist;
    wobei Cy3, wenn vorhanden, C3-C6-Cycloalkyl, C2-C5-Heterocycloalkyl, oder Aryl ist, und mit 0, 1, 2 oder 3 Gruppen substituiert ist, die unabhängig ausgewählt sind aus Halogen, -NH2, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, und (C1-C4)(C1-C4)-Dialkylamino;
    wobei A O, NR6a, oder CHR6b ist;
    wobei R6a Wasserstoff oder C1-C4-Alkyl ist; und
    wobei R6b Wasserstoff, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, (C1-C4)(C1-C4)-Dialkylamino, oder-CO2H ist;
    wobei R7 Wasserstoff, Halogen, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, oder C1-C4-Alkoxy ist;
    wobei jedes Auftreten von R8a und R8b, wenn vorhanden, unabhängig Wasserstoff, C1-C4-Alkyl, C1-C4-Halogenalkyl, Phenyl, oder-CO2H ist;
    oder wobei p 1 ist und jedes von R8a und R8b zusammen =O aufweist; und
    wobei R9 Wasserstoff, C1-C4-Alkyl, oder Cy4 ist,
    wobei Cy4, wenn vorhanden, C3-C6-Cycloalkyl, C2-C5-Heterocycloalkyl, oder Aryl ist, und mit 0, 1, 2 oder 3 Gruppen substituiert ist, die unabhängig ausgewählt sind aus Halogen, -NH2, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, und (C1-C4)(C1-C4)-Dialkylamino,
    oder ein pharmazeutisch verträgliches Salz davon.
  8. Pharmazeutische Zusammensetzung nach Anspruch 7, wobei p 1 ist; R1 -NH2, - OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, (C1-C4)(C1-C4)-Dialkylamino, oder Cy1 ist; jedes von R5a, R5b, R5c, und R5d unabhängig Wasserstoff, Halogen, -NH2, -CN, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, (C1-C4)(C1-C4)-Dialkylamino, -CO2(C1-C4-Alkyl), - CO2H, -CO2NH2, -NHC(O)Cy3, -NHC(O)(C1-C4-Alkyl), oder Cy3; und R8a Wasserstoff ist und R8b Wasserstoff, C1-C4-Alkyl, oder C1-C4-Halogenalkyl ist;
    oder wobei n 1 ist;
    oder wobei R5c Wasserstoff, Halogen, -NH2, -OH, C1-C4-Alkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, oder (C1-C4)(C1-C4)-Dialkylamino ist;
    oder wobei Cy3, wenn vorhanden, C3-C6-Cycloalkyl oder Aryl ist, und mit 0, 1, 2 oder 3 Gruppen substituiert ist, die unabhängig ausgewählt sind aus Halogen, -NH2, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, und (C1-C4)(C1-C4)-Dialkylamino.
  9. Pharmazeutische Zusammensetzung nach Anspruch 7, umfassend einen pharmazeutisch verträglichen Träger und eine therapeutisch wirksame Menge von mindestens einer Verbindung, die eine durch eine Formel dargestellte Struktur aufweist:
    Figure imgb0397
    wobei n 0, 1, oder 2 ist;
    wobei q 0 oder 1 ist;
    wobei R1-NH2, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Hydroxyalkyl, C1-C4-Alkylamino, (C1-C4)(C1-C4)-Dialkylamino, -(C1-C4-Alkyl)(C1-C4-Alkoxy), -(C1-C4-Alkyl)CO2H, oder Cy1 ist;
    wobei Cy1, wenn vorhanden, C3-C6-Cycloalkyl, C2-C5-Heterocycloalkyl, oder Aryl ist, und mit 0, 1, 2 oder 3 Gruppen substituiert ist, die unabhängig ausgewählt sind aus Halogen, -NH2, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, und (C1-C4)(C1-C4)-Dialkylamino;
    wobei R2 Wasserstoff oder C1-C4-Alkyl ist, oder wobei jedes von R1 und R2 kovalent miteinander verbunden ist und zusammen mit den Zwischenatomen ein 3- bis 6-gliedriges Heterocycloalkyl aufweist, das mit 0, 1, 2 oder 3 Gruppen substituiert ist, die unabhängig ausgewählt sind aus Halogen, -NH2, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, und (C1-C4)(C1-C4)-Dialkylamino;
    wobei R3 Wasserstoff oder C1-C4-Alkyl ist, oder wobei jedes von R1 und R3 kovalent miteinander verbunden ist und zusammen mit den Zwischenatomen ein 5- bis 7-gliedriges Heterocycloalkyl aufweist, das mit 0, 1, 2 oder 3 Gruppen substituiert ist, die unabhängig ausgewählt sind aus Halogen, -NH2, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, und (C1-C4)(C1-C4)-Dialkylamino;
    wobei R4 Wasserstoff, Halogen, -NH2, -OH, C1-C4-Alkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, (C1-C4)(C1-C4)-Dialkylamino, oder Cy2 ist;
    wobei Cy2, wenn vorhanden, C3-C6-Cycloalkyl, C2-C5-Heterocycloalkyl, oder Aryl ist, und mit 0, 1, 2 oder 3 Gruppen substituiert ist, die unabhängig ausgewählt sind aus Halogen, -NH2, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, und (C1-C4)(C1-C4)-Dialkylamino;
    wobei jedes von R5a, R5b, und R5d unabhängig Wasserstoff, Halogen, -NH2, - CN, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Haloalkoxy, C1-C4-Alkylamino, (C1-C4)(C1-C4)-Dialkylamino, -CO2(C1-C4-Alkyl), -CO2H, -CO2NH2, -NHC(O)Cy3, -NHC(O)(C1-C4-Alkyl), oder Cy3 ist;
    wobei Cy3, wenn vorhanden, C3-C6-Cycloalkyl, C2-C5-Heterocycloalkyl, oder Aryl ist, und mit 0, 1, 2 oder 3 Gruppen substituiert ist, die unabhängig ausgewählt sind aus Halogen, -NH2, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, und (C1-C4)(C1-C4)-Dialkylamino;
    wobei R5c Wasserstoff, Halogen, -NH2, -OH, -CN, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Haloalkoxy, C1-C4-Alkylamino, (C1-C4)(C1-C4)-Dialkylamino, -CO2(C1-C4-Alkyl), -CO2H, -CO2NH2, - NHC(O)Cy3, -NHC(O)(C1-C4-Alkyl), oder Aryl ist, substituiert mit 0, 1, 2 oder 3 Gruppen, unabhängig ausgewählt aus Halogen, -NH2, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, und (C1-C4)(C1-C4)-Dialkylamino;
    wobei A O, NR6a, oder CHR6b ist;
    wobei R6a Wasserstoff oder C1-C4-Alkyl ist; und
    wobei R6b Wasserstoff, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, (C1-C4)(C1-C4)-Dialkylamino, oder-CO2H ist;
    wobei R7 Wasserstoff, Halogen, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, oder C1-C4-Alkoxy ist;
    vorausgesetzt, dass R5b Morpholinyl ist und R1 Thiophenyl oder Thiazolyl ist, dann ist q 1 und mindestens einer der Reste R5a, R5c und R5d ist nicht Wasserstoff,
    oder ein pharmazeutisch verträgliches Salz davon.
  10. Pharmazeutische Zusammensetzung nach Anspruch 9, wobei R1 -NH2, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, (C1-C4)(C1-C4)-Dialkylamino, oder Cy1 ist; jedes von R5a, R5b, und R5d unabhängig Wasserstoff, Halogen, -NH2, -CN, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, (C1-C4)(C1-C4)-Dialkylamino, -CO2(C1-C4-Alkyl), -CO2H, -CO2NH2, -NHC(O)Cy3, -NHC(O)(C1-C4-Alkyl), oder Cy3 ist; und R5c Wasserstoff, Halogen, -NH2, -OH, -CN, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Haloalkoxy, C1-C4-Alkylamino, (C1-C4)(C1-C4)-Dialkylamino, -CO2(C1-C4-Alkyl), -CO2H, -CO2NH2, -NHC(O)Cy3, - NHC(O)(C1-C4-Alkyl), oder Aryl ist, substituiert mit 0, 1, 2 oder 3 Gruppen, unabhängig ausgewählt aus Halogen, -NH2, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, und (C1-C4)(C1-C4)-Dialkylamino;
    oder wobei n 1 ist;
    oder wobei R5c Wasserstoff, Halogen, -NH2, -OH, C1-C4-Alkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, oder (C1-C4)(C1-C4)-Dialkylamino ist;
    oder wobei jedes von R5a, R5b, R5c, und R5d unabhängig Wasserstoff, Halogen, - NH2, -OH, C1-C4-Alkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, oder (C1-C4)(C1-C4)-Dialkylamino ist.
  11. Pharmazeutische Zusammensetzung, umfassend einen pharmazeutisch verträglichen Träger und eine therapeutisch wirksame Menge von mindestens einer Verbindung, die eine Struktur aufweist, die durch eine Formel dargestellt ist, die ausgewählt ist aus:
    Figure imgb0398
    wobei n 0, 1, oder 2 ist;
    wobei p 0, 1, 2, 3, oder 4 ist;
    wobei q 0 oder 1 ist;
    wobei R1-NH2, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Hydroxyalkyl, C1-C4-Alkylamino, (C1-C4)(C1-C4)-Dialkylamino, -(C1-C4-Alkyl)(C1-C4-Alkoxy), -(C1-C4-Alkyl)CO2H, oder Cy1 ist;
    wobei Cy1, wenn vorhanden, C3-C6-Cycloalkyl, C2-C5-Heterocycloalkyl, oder Aryl ist, und mit 0, 1, 2 oder 3 Gruppen substituiert ist, die unabhängig ausgewählt sind aus Halogen, -NH2, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, und (C1-C4)(C1-C4)-Dialkylamino;
    wobei R2 Wasserstoff oder C1-C4-Alkyl ist, oder wobei jedes von R1 und R2 kovalent miteinander verbunden ist und zusammen mit den Zwischenatomen ein 3- bis 6-gliedriges Heterocycloalkyl aufweist, das mit 0, 1, 2 oder 3 Gruppen substituiert ist, die unabhängig ausgewählt sind aus Halogen, -NH2, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, und (C1-C4)(C1-C4)-Dialkylamino;
    wobei R3 Wasserstoff oder C1-C4-Alkyl ist, oder wobei jedes von R1 und R3 kovalent miteinander verbunden ist und zusammen mit den Zwischenatomen ein 5- bis 7-gliedriges Heterocycloalkyl aufweist, das mit 0, 1, 2 oder 3 Gruppen substituiert ist, die unabhängig ausgewählt sind aus Halogen, -NH2, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, und (C1-C4)(C1-C4)-Dialkylamino;
    wobei R4 Wasserstoff, Halogen, -NH2, -OH, C1-C4-Alkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, (C1-C4)(C1-C4)-Dialkylamino, oder Cy2 ist;
    wobei Cy2, wenn vorhanden, C3-C6-Cycloalkyl, C2-C5-Heterocycloalkyl, oder Aryl ist, und mit 0, 1, 2 oder 3 Gruppen substituiert ist, die unabhängig ausgewählt sind aus Halogen, -NH2, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, und (C1-C4)(C1-C4)-Dialkylamino;
    wobei jedes von R5a, R5b, R5c, und R5d unabhängig Wasserstoff, Halogen, -NH2, -CN, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Haloalkoxy, C1-C4-Alkylamino, (C1-C4)(C1-C4)-Dialkylamino, -CO2(C1-C4-Alkyl), -CO2H, -CO2NH2, -NHC(O)Cy3, -NHC(O)(C1-C4-Alkyl), oder Cy3 ist;
    wobei Cy3, wenn vorhanden, C3-C6-Cycloalkyl, C2-C5-Heterocycloalkyl, oder Aryl ist, und mit 0, 1, 2 oder 3 Gruppen substituiert ist, die unabhängig ausgewählt sind aus Halogen, -NH2, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, und (C1-C4)(C1-C4)-Dialkylamino;
    wobei A O, NR6a, oder CHR6b ist;
    wobei R6a Wasserstoff oder C1-C4-Alkyl ist; und
    wobei R6b Wasserstoff, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, (C1-C4)(C1-C4)-Dialkylamino, oder-CO2H ist;
    wobei R7 Wasserstoff, Halogen, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, oder C1-C4-Alkoxy ist;
    wobei jedes Auftreten von R8a und R8b, wenn vorhanden, unabhängig Wasserstoff, C1-C4-Alkyl, C1-C4-Halogenalkyl, Phenyl, oder-CO2H ist;
    oder wobei p 1 ist und jedes von R8a und R8b zusammen =O aufweist; und
    wobei R9 Wasserstoff, C1-C4-Alkyl, oder Cy4 ist,
    wobei Cy4, wenn vorhanden, C3-C6-Cycloalkyl, C2-C5-Heterocycloalkyl, oder Aryl ist, und mit 0, 1, 2 oder 3 Gruppen substituiert ist, die unabhängig ausgewählt sind aus Halogen, -NH2, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, und (C1-C4)(C1-C4)-Dialkylamino,
    oder ein pharmazeutisch verträgliches Salz davon.
  12. Verbindung, die eine Struktur aufweist, die durch eine Formel dargestellt ist:
    Figure imgb0399
    wobei n 0, 1, oder 2 ist;
    wobei p 1, 2, 3, oder 4 ist;
    wobei q 0 oder 1 ist;
    wobei R1-OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Hydroxyalkyl, C1-C4-Alkylamino, (C1-C4)(C1-C4)-Dialkylamino, -(C1-C4-Alkyl)(C1-C4-Alkoxy), -(C1-C4-Alkyl)CO2H, oder Cy1 ist;
    wobei Cy1, wenn vorhanden, C3-C6-Cycloalkyl, C2-C5-Heterocycloalkyl, oder Aryl ist, und mit 0, 1, 2 oder 3 Gruppen substituiert ist, die unabhängig ausgewählt sind aus Halogen, -NH2, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, und (C1-C4)(C1-C4)-Dialkylamino;
    wobei R2 Wasserstoff oder C1-C4-Alkyl ist, oder wobei jedes von R1 und R2 kovalent miteinander verbunden ist und zusammen mit den Zwischenatomen ein 3- bis 6-gliedriges Heterocycloalkyl aufweist, das mit 0, 1, 2 oder 3 Gruppen substituiert ist, die unabhängig ausgewählt sind aus Halogen, -NH2, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, und (C1-C4)(C1-C4)-Dialkylamino;
    wobei R3 Wasserstoff oder C1-C4-Alkyl ist, oder wobei jedes von R1 und R3 kovalent miteinander verbunden ist und zusammen mit den Zwischenatomen ein 5- bis 7-gliedriges Heterocycloalkyl aufweist, das mit 0, 1, 2 oder 3 Gruppen substituiert ist, die unabhängig ausgewählt sind aus Halogen, -NH2, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, und (C1-C4)(C1-C4)-Dialkylamino;
    wobei R4 Wasserstoff, Halogen, -NH2, -OH, C1-C4-Alkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, (C1-C4)(C1-C4)-Dialkylamino, oder Cy2 ist;
    wobei Cy2, wenn vorhanden, C3-C6-Cycloalkyl, C2-C5-Heterocycloalkyl, oder Aryl ist, und mit 0, 1, 2 oder 3 Gruppen substituiert ist, die unabhängig ausgewählt sind aus Halogen, -NH2, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, und (C1-C4)(C1-C4)-Dialkylamino;
    wobei jedes von R5a, R5b, R5c, und R5d unabhängig Wasserstoff, Halogen, -NH2, -CN, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Haloalkoxy, C1-C4-Alkylamino, (C1-C4)(C1-C4)-Dialkylamino, -CO2(C1-C4-Alkyl), -CO2H, -CO2NH2, -NHC(O)Cy3, -NHC(O)(C1-C4-Alkyl), oder Cy3 ist;
    wobei Cy3, wenn vorhanden, C3-C6-Cycloalkyl, C2-C5-Heterocycloalkyl, oder Aryl ist, und mit 0, 1, 2 oder 3 Gruppen substituiert ist, die unabhängig ausgewählt sind aus Halogen, -NH2, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, und (C1-C4)(C1-C4)-Dialkylamino;
    wobei A O, NR6a, oder CHR6b ist;
    wobei R6a Wasserstoff oder C1-C4-Alkyl ist; und
    wobei R6b Wasserstoff, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, (C1-C4)(C1-C4)-Dialkylamino, oder-CO2H ist;
    wobei R7 Wasserstoff, Halogen, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, oder C1-C4-Alkoxy ist; und
    wobei jedes Auftreten von R8a und R8b, wenn vorhanden, unabhängig Wasserstoff, C1-C4-Alkyl, C1-C4-Halogenalkyl, Phenyl, oder-CO2H ist;
    oder wobei p 1 ist und jedes von R8a und R8b zusammen =O aufweist; vorausgesetzt, dass R1 Methyl ist und jedes von R3 und R4 Wasserstoff ist, dann ist jedes von R5a, R5b, R5c, und R5d unabhängig Wasserstoff, Fluor, -NH2, - OH, C1-C4-Alkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, (C1-C4)(C1-C4)-Dialkylamino, oder Cy3, und
    vorausgesetzt, dass n 1 ist, p 1 ist, q 0 ist, A CHR6b ist, und R1 Methyl ist, dann sind mindestens zwei von R4, R5a, R5b, R5c, und R5d nicht Wasserstoff,
    oder ein pharmazeutisch verträgliches Salz davon.
  13. Verbindung nach Anspruch 12, wobei p 1 ist; R1 -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, (C1-C4)(C1-C4)-Dialkylamino, oder Cy1 ist; jedes von R5a, R5b, R5c, und R5d unabhängig Wasserstoff, Halogen, -NH2, - CN, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, (C1-C4)(C1-C4)-Dialkylamino, -CO2(C1-C4-Alkyl), -CO2H, -CO2NH2, -NHC(O)Cy3, - NHC(O)(C1-C4-Alkyl), oder Cy3 ist; und R8a Wasserstoff ist und R8b Wasserstoff, C1-C4-Alkyl, oder C1-C4-Halogenalkyl ist;
    oder wobei R5c Fluor ist;
    oder wobei R1 Methyl ist, jedes von R3 und R4 Wasserstoff ist, und jedes von R5a, R5b, R5c, und R5d unabhängig Wasserstoff, -NH2, -OH, C1-C4-Alkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, (C1-C4)(C1-C4)-Dialkylamino, oder Cy3 ist; oder wobei R1 Methyl ist, jedes von R3 und R4 Wasserstoff ist, und R5b Fluor ist;
    oder wobei R5c Wasserstoff, Halogen, -NH2, -OH, C1-C4-Alkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, oder (C1-C4)(C1-C4)-Dialkylamino ist; oder wobei Cy3, wenn vorhanden, C3-C6-Cycloalkyl oder Aryl ist, und mit 0, 1, 2 oder 3 Gruppen substituiert ist, die unabhängig ausgewählt sind aus Halogen, -NH2, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, und (C1-C4)(C1-C4)-Dialkylamino.
  14. Verbindung nach Anspruch 12, die eine Struktur aufweist, die durch eine Formel dargestellt ist:
    Figure imgb0400
    wobei n 0, 1, oder 2 ist;
    wobei q 0 oder 1 ist;
    wobei R1-NH2, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Hydroxyalkyl, C1-C4-Alkylamino, (C1-C4)(C1-C4)-Dialkylamino, -(C1-C4-Alkyl)(C1-C4-Alkoxy), -(C1-C4-Alkyl)CO2H, oder Cy1 ist;
    wobei Cy1, wenn vorhanden, C3-C6-Cycloalkyl, C2-C5-Heterocycloalkyl, oder Aryl ist, und mit 0, 1, 2 oder 3 Gruppen substituiert ist, die unabhängig ausgewählt sind aus Halogen, -NH2, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, und (C1-C4)(C1-C4)-Dialkylamino;
    wobei R2 Wasserstoff oder C1-C4-Alkyl ist, oder wobei jedes von R1 und R2 kovalent miteinander verbunden ist und zusammen mit den Zwischenatomen ein 3- bis 6-gliedriges Heterocycloalkyl aufweist, das mit 0, 1, 2 oder 3 Gruppen substituiert ist, die unabhängig ausgewählt sind aus Halogen, -NH2, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, und (C1-C4)(C1-C4)-Dialkylamino;
    wobei R3 Wasserstoff oder C1-C4-Alkyl ist, oder wobei jedes von R1 und R3 kovalent miteinander verbunden ist und zusammen mit den Zwischenatomen ein 5- bis 7-gliedriges Heterocycloalkyl aufweist, das mit 0, 1, 2 oder 3 Gruppen substituiert ist, die unabhängig ausgewählt sind aus Halogen, -NH2, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, und (C1-C4)(C1-C4)-Dialkylamino;
    wobei R4 Wasserstoff, Halogen, -NH2, -OH, C1-C4-Alkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, (C1-C4)(C1-C4)-Dialkylamino, oder Cy2 ist;
    wobei Cy2, wenn vorhanden, C3-C6-Cycloalkyl, C2-C5-Heterocycloalkyl, oder Aryl ist, und mit 0, 1, 2 oder 3 Gruppen substituiert ist, die unabhängig ausgewählt sind aus Halogen, -NH2, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, und (C1-C4)(C1-C4)-Dialkylamino;
    wobei jedes von R5a, R5b, und R5d unabhängig Wasserstoff, Halogen, -NH2, - CN, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Haloalkoxy, C1-C4-Alkylamino, (C1-C4)(C1-C4)-Dialkylamino, -CO2(C1-C4-Alkyl), -CO2H, -CO2NH2, -NHC(O)Cy3, -NHC(O)(C1-C4-Alkyl), oder Cy3 ist;
    wobei Cy3, wenn vorhanden, C3-C6-Cycloalkyl, C2-C5-Heterocycloalkyl, oder Aryl ist, und mit 0, 1, 2 oder 3 Gruppen substituiert ist, die unabhängig ausgewählt sind aus Halogen, -NH2, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, und (C1-C4)(C1-C4)-Dialkylamino;
    wobei R5c Wasserstoff, Halogen, -CN, -NH2, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Haloalkoxy, C1-C4-Alkylamino, (C1-C4)(C1-C4)-Dialkylamino, -CO2(C1-C4-Alkyl), -CO2H, -CO2NH2, - NHC(O)Cy3, -NHC(O)(C1-C4-Alkyl), oder Aryl ist, substituiert mit 0, 1, 2 oder 3 Gruppen, unabhängig ausgewählt aus Halogen, -NH2, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, und (C1-C4)(C1-C4)-Dialkylamino;
    wobei A O, NR6a, oder CHR6b ist;
    wobei R6a Wasserstoff oder C1-C4-Alkyl ist;
    wobei R6b Wasserstoff, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, (C1-C4)(C1-C4)-Dialkylamino, oder-CO2H ist; und
    wobei R7 Wasserstoff, Halogen, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, oder C1-C4-Alkoxy ist;
    vorausgesetzt, dass R5b Morpholinyl ist und R1 Thiophenyl oder Thiazolyl ist, dann ist q 1 und mindestens eines von R5a, R5c, und R5d ist nicht Wasserstoff;
    vorausgesetzt, dass q 0 ist, dann ist Cy1 nicht Aryl; und
    vorausgesetzt, dass mindestens eines von R5a, R5b, R5c, und R5d nicht Wasserstoff ist,
    oder ein pharmazeutisch verträgliches Salz davon.
  15. Verbindung nach Anspruch 14, wobei R1-NH2, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, (C1-C4)(C1-C4)-Dialkylamino, oder Cy1 ist; jedes von R5a, R5b ist, und R5d unabhängig Wasserstoff, Halogen, -NH2, -CN, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, (C1-C4)(C1-C4)-Dialkylamino, -CO2(C1-C4-Alkyl), -CO2H, -CO2NH2, -NHC(O)Cy3, - NHC(O)(C1-C4-Alkyl), oder Cy3 ist; und R5c Wasserstoff, Halogen, -NH2, -OH, -CN, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Haloalkoxy, C1-C4-Alkylamino, (C1-C4)(C1-C4)-Dialkylamino, -CO2(C1-C4-Alkyl), -CO2H, -CO2NH2, - NHC(O)Cy3, -NHC(O)(C1-C4-Alkyl), oder Aryl ist, substituiert mit 0, 1, 2 oder 3 Gruppen, unabhängig ausgewählt aus Halogen, -NH2, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, und (C1-C4)(C1-C4)-Dialkylamino;
    oder wobei n 1 ist;
    oder wobei R5c Wasserstoff, Halogen, -NH2, -OH, -C1-C4-Alkoxy, C1-C4-Alkylamino, oder (C1-C4)(C1-C4)-Dialkylamino ist;
    oder wobei jedes von R5a, R5b, R5c, und R5d unabhängig Wasserstoff, Halogen, - NH2, -OH, C1-C4-Alkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, oder (C1-C4)(C1-C4)-Dialkylamino ist.
  16. Verbindung, die eine Struktur aufweist, die durch eine Formel dargestellt ist, die ausgewählt ist aus:
    Figure imgb0401
    wobei n 0, 1, oder 2 ist;
    wobei p 0, 1, 2, 3, oder 4 ist;
    wobei q 0 oder 1 ist;
    wobei R1-NH2, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Hydroxyalkyl, C1-C4-Alkylamino, (C1-C4)(C1-C4)-Dialkylamino, -(C1-C4-Alkyl)(C1-C4-Alkoxy), -(C1-C4-Alkyl)CO2H, oder Cy1 ist;
    wobei Cy1, wenn vorhanden, C3-C6-Cycloalkyl, C2-C5-Heterocycloalkyl, oder Aryl ist, und mit 0, 1, 2 oder 3 Gruppen substituiert ist, die unabhängig ausgewählt sind aus Halogen, -NH2, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, und (C1-C4)(C1-C4)-Dialkylamino;
    wobei R2 Wasserstoff oder C1-C4-Alkyl ist, oder wobei jedes von R1 und R2 kovalent miteinander verbunden ist und zusammen mit den Zwischenatomen ein 3- bis 6-gliedriges Heterocycloalkyl aufweist, das mit 0, 1, 2 oder 3 Gruppen substituiert ist, die unabhängig ausgewählt sind aus Halogen, -NH2, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, und (C1-C4)(C1-C4)-Dialkylamino;
    wobei R3 Wasserstoff oder C1-C4-Alkyl ist, oder wobei jedes von R1 und R3 kovalent miteinander verbunden ist und zusammen mit den Zwischenatomen ein 5- bis 7-gliedriges Heterocycloalkyl aufweist, das mit 0, 1, 2 oder 3 Gruppen substituiert ist, die unabhängig ausgewählt sind aus Halogen, -NH2, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, und (C1-C4)(C1-C4)-Dialkylamino;
    wobei R4 Wasserstoff, Halogen, -NH2, -OH, C1-C4-Alkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, (C1-C4)(C1-C4)-Dialkylamino, oder Cy2 ist;
    wobei Cy2, wenn vorhanden, C3-C6-Cycloalkyl, C2-C5-Heterocycloalkyl, oder Aryl ist, und mit 0, 1, 2 oder 3 Gruppen substituiert ist, die unabhängig ausgewählt sind aus Halogen, -NH2, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, und (C1-C4)(C1-C4)-Dialkylamino;
    wobei jedes von R5a, R5b, R5c, und R5d unabhängig Wasserstoff, Halogen, -NH2, -CN, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Haloalkoxy, C1-C4-Alkylamino, (C1-C4)(C1-C4)-Dialkylamino, -CO2(C1-C4-Alkyl), -CO2H, -CO2NH2, -NHC(O)Cy3, -NHC(O)(C1-C4-Alkyl), oder Cy3 ist;
    wobei Cy3, wenn vorhanden, C3-C6-Cycloalkyl, C2-C5-Heterocycloalkyl, oder Aryl ist, und mit 0, 1, 2 oder 3 Gruppen substituiert ist, die unabhängig ausgewählt sind aus Halogen, -NH2, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, und (C1-C4)(C1-C4)-Dialkylamino;
    wobei A O, NR6a, oder CHR6b ist;
    wobei R6a Wasserstoff oder C1-C4-Alkyl ist; und
    wobei R6b Wasserstoff, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, (C1-C4)(C1-C4)-Dialkylamino, oder-CO2H ist;
    wobei R7 Wasserstoff, Halogen, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, oder C1-C4-Alkoxy ist;
    wobei jedes Auftreten von R8a und R8b, wenn vorhanden, unabhängig Wasserstoff, C1-C4-Alkyl, C1-C4-Halogenalkyl, Phenyl, oder-CO2H ist;
    oder wobei p 1 ist und jedes von R8a und R8b zusammen =O aufweist; und
    wobei R9 Wasserstoff, C1-C4-Alkyl, oder Cy4 ist,
    wobei Cy4, wenn vorhanden, C3-C6-Cycloalkyl, C2-C5-Heterocycloalkyl, oder Aryl ist, und mit 0, 1, 2 oder 3 Gruppen substituiert ist, die unabhängig ausgewählt sind aus Halogen, -NH2, -OH, C1-C4-Alkyl, C1-C4-Halogenalkyl, C1-C4-Alkoxy, C1-C4-Alkylamino, und (C1-C4)(C1-C4)-Dialkylamino,
    oder ein pharmazeutisch verträgliches Salz davon.
  17. Pharmazeutische Zusammensetzung nach einem der Ansprüche 7 bis 11 oder eine Verbindung nach einem der Ansprüche 12 bis 16 zur Verwendung in einem Verfahren zur Behandlung einer Störung, die mit erhöhtem TXNIP oder erhöhtem Glucagon in einem Säuger assoziiert ist, wobei die Behandlung eine Verabreichung einer therapeutisch wirksamen Menge von mindestens einer pharmazeutischen Zusammensetzung nach einem der Ansprüche 7 bis 11 oder mindestens einer Verbindung nach einem der Ansprüche 12 bis 16 an den Säuger aufweist, wobei die Störung Diabetes oder eine mit Diabetes verbundene Störung ist.
  18. Pharmazeutische Zusammensetzung nach einem der Ansprüche 7 bis 11 oder eine Verbindung nach einem der Ansprüche 12 bis 16 zur Verwendung in einem Verfahren zur Behandlung von Diabetes oder einer mit Diabetes in Zusammenhang stehenden Störung in einem Säuger nach Anspruch 17 durch Senkung hepatischer Glukoseproduktion in einem Säuger, das diese benötigt, umfassend eine Verabreichung einer therapeutisch wirksamen Menge mindestens einer pharmazeutischen Zusammensetzung nach einem der Ansprüche 7 bis 11 oder mindestens einer Verbindung nach einem der Ansprüche 12 bis 16 an den Säuger.
  19. Pharmazeutische Zusammensetzung nach einem der Ansprüche 7 bis 11 oder eine Verbindung nach einem der Ansprüche 12 bis 16 zur Verwendung in einem Verfahren zur Behandlung von Hyperlipidämie in einem Säuger nach Anspruch 17, wobei die Behandlung eine Verabreichung einer therapeutisch wirksamen Menge von mindestens einer pharmazeutischen Zusammensetzung nach einem der Ansprüche 7 bis 11 oder mindestens einer Verbindung nach einem der Ansprüche 12 bis 16 an den Säuger aufweist.
  20. Pharmazeutische Zusammensetzung nach einem der Ansprüche 7 bis 11 oder eine Verbindung nach einem der Ansprüche 12 bis 16 zur Verwendung in einem Verfahren zur Behandlung einer Fettlebererkrankung in einem Säuger nach Anspruch 17, wobei die Behandlung eine Verabreichung einer therapeutisch wirksamen Menge von mindestens einer pharmazeutischen Zusammensetzung nach einem der Ansprüche 7 bis 11 oder mindestens einer Verbindung nach einem der Ansprüche 12 bis 16 an den Säuger aufweist, wobei vorzugsweise die Fettlebererkrankung eine nichtalkoholische Fettlebererkrankung ist.
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